Polymeric biomaterials derived from phenolic monomers and their medical uses

ABSTRACT

Disclosed are new classes of diphenol compounds, derived from tyrosol or tyrosol analogues and hydroxybenzoic acid, which are useful as monomers for preparation of biocompatible polymers. Also disclosed are biocompatible polymers prepared from these monomeric diphenol compounds, including novel biodegradable and/or bioresorbable polymers of formula. These biocompatible polymers or polymer compositions with enhanced bioresorbabilty and processibility are useful in a variety of medical applications, such as in medical devices and controlled-release therapeutic compositions. The invention also provides methods for preparing these monomeric diphenol compounds and biocompatible polymers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) toInternational Patent Application No. PCT/IB15/059967 filed Dec. 23,2015, all of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to new classes of monomeric phenolcompounds useful for preparation of biocompatible polymers andbiocompatible polymers prepared therefrom, including novel biodegradableand/or bioresorbable polymers. These polymers, while not limitedthereto, may be adapted for radio-opacity and are useful for medicaldevice applications and controlled release therapeutic formulations.

BACKGROUND OF THE INVENTION

The rapidly evolving field of bioengineering has created a demand for adiverse library of different types of polymers offering a wide varietyof choice of physical, mechanical, chemical and physiologicalproperties. It is desirable that libraries of many different materialsbe available so that the specific polymer properties can be optimallymatched with the requirements of the specific applications underdevelopment.

Examples of polymers suitable for various bioengineering applicationsinclude those described in U.S. Pat. Nos. 5,099,060; 5,665,831;5,916,998 and 6,475,477, along with the polymers described in U.S.Patent Publication Nos. 2006/0024266, 2006/0034769, 2013/0203713 and2015/0045451. There are numerous applications in which it is considereddesirable for an implanted medical device to maintain its integrity andperformance characteristics for extended periods of time, even underdemanding mechanical conditions such as repeated mechanical flexure.

Although many types of bioresorbable and/or biodegradable polymers areknown, in most of these polymers diphenolic monomers are prepared bylinking two suitably protected tyrosine molecules or tyrosine analogsvia an amide linkage. These amide linkages do not degrade hydrolyticallyunder physiological conditions and therefore the monomers which have lowsolubility in water, dissolve very slowly. Further, due to hydrogenbonding of amide hydrogen the melt viscosity of the polymers derivedfrom these monomers is very high, which makes thermal processing moredifficult. In addition, bioresorbtion and/or biodegradation tend toalter mechanical properties in unpredictable ways that are notnecessarily linearly related to each other.

Thus, there is a need for biocompatible polymers having desirablebioresorbability and biodegradability as well as good processibilityunder thermal conditions. There remains a need for nontoxic polyarylateshaving a moderate rate of bioerosion, suitable for use astissue-compatible materials for biomedical uses.

SUMMARY OF THE INVENTION

The present invention addresses the foregoing need by providing newmonomers useful for the preparation of the desired biocompatiblepolymers and various types of such polymers useful for making theimplantable medical devices.

The present invention broadly relates to diphenolic monomers andbioerodible polymers synthesized using such monomers. In variousembodiments, the diphenolic monomers comprise the elements of tyrosineor tyrosol, and hydroxybenzoic acid. In particular, in one preferredaspect the present invention relates to bioerodible polycarbonates andpolyarylates derived from the naturally occurring4-(2-hydroxylethyl)phenol (or “tyrosol”) and phosgene and/orbiocompatible dicarboxylic acids. In one embodiment the monomers aretyrosol-containing diphenolic monomers where one of the phenolic OHgroups is from tyrosol.

Polymers

In one aspect the present invention provides biocompatible polymerscomprising a repeating structural unit of Formula (I):

wherein X¹ and X², at each occurrence, are independently halogen (F, Cl,Br, or I); wherein y1 and y2 have values independently selected from 0,1, 2, 3 and 4; and

wherein L is —R1-A-R2-, such that:

(a) R1 and R2 are each independently selected from a bond, or astraight-chain or branched, saturated or unsaturated, substituted orunsubstituted, alkylene, alkenylene, alkylarylenoxy, heteroalkylene andheteroalkenylene containing up to 12 carbon atoms, wherein saidalkylene, alkenylene, heteroalkylene and heteroalkenylene may:

(i) optionally comprise one, two or three heteroatoms independentlyselected from O, NRz and S; or

(ii) optionally contain a pendant Z group selected from the groupconsisting of —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶, —COOR⁷, and—CONR^(x)R^(y), wherein R⁵, R⁶, R⁷, R^(x) and R^(y), at each occurrence,are independently selected from hydrogen, alkyl, aryl, alkylaryl,arylalkyl, heteroalkyl, and heteroalkylaryl group containing up to 30carbon atoms, wherein the heteroalkyl group contains from 1 to 10heteroatoms independently selected from O, N and S and theheteroalkylaryl group contains from 1 to 3 heteroatoms independentlyselected from O, N and S; and

(b) A is a linking group selected from:

wherein

(i) R³ is selected from the group consisting of hydrogen, C₁-C₃₀ alkyl,C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ hetero alkynyl;

(ii) R⁴ is selected from the group consisting of C₁-C₃₀ alkylene, C₂-C₃₀alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene;

(iii) R^(4a) is selected from the group consisting of C₁-C₃₀ alkylene,C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene.

In various embodiments according to Formula (I) above, the heteroatom inthe heteroalkyl and/or heteroalkylaryl group is N in the form of aNR^(z) group, wherein IV is selected from the group consisting of H,C₁-C₃₀ alkyl, and arylalkyl containing up to 30 carbon atoms.

In various embodiments, R^(x) in the definition of A, R2 and R1 asincluded in L in

Formula (I) is an alkyl group, e.g., a branched or unbranched C₁-C₆alkyl.

(i) For example, in an embodiment, R^(x) in Formula (I) is a methyl.

(ii) For example, in various embodiments, R¹ is —(CH₂)_(n)— and R² areeach independently —(CH₂)_(m)— and —(CH₂)_(n)—, respectively, where nand m are each independently is an integer in the range of zero to 12.

(iii) For example, in an embodiment, R¹ is —(CH₂)_(m)— and R² is—(CH₂)_(n)—, and n and m are each independently 0, 1 or 2.

(iv) In some embodiments, R¹ is —O—(CH₂)_(n)— or —O—C₆H₄—(CH₂)_(n)—,where the —C₆H₄— is optionally substituted phenyl (e.g., optionallysubstituted with 1 or 2 halogens such as Br and/or I) and n and m areeach independently is an integer in the range of zero to 12. (e.g., 0, 1or 2).

(v) Similarly, in some embodiments, R² is independently —(CH₂)_(n)—O— or—(CH₂)_(n)—C6H₄—O—, where the —C₆H₄— is independently optionallysubstituted phenyl (e.g., optionally substituted with 1 or 2 halogenssuch as Br and/or I); and n and m are each independently integers in therange of zero to 12. (e.g., 0, 1 or 2).

X¹ and X² in Formula (I) can be independently selected to be any halogenatom. In an embodiment, X¹ and X² in Formula (I) are each I. In anembodiment, X¹ and X² in Formula (I) are each Br. In some embodiments,the X¹ and X² groups on the polymer comprising a recurring unit ofFormula (I) are iodine.

In a particular exemplary embodiment according to Formula (I), X¹ and X²are each I; y1 and y2 may independently be 0, 1, or 2; and L may beselected so that R¹ is —(CH₂)₂—; R² is a bond, and A is

so that a repeating structural unit is as follows, in which the alcoholportion of the ester is derived from tyrosol or iodinated tyrosol:

Those skilled in the art will appreciate that the presence of oxygenatoms on both ends of the repeating structural unit of Formula (I) doesnot imply end-to-end linkage of such repeating units to formoxygen-oxygen bonds. Instead, it will be appreciated that the polymercontaining the repeating structural unit of Formula (I) can also containone or more other repeating units. For example, in another aspect thepresent invention provides polymers containing the repeating structuralunit of Formula (I) and further containing recurring units representedby A¹. Examples of such polymers include polycarbonates, polyarylates,polyiminocarbonates, polyphosphazenes and polyphosphoesters, comprisingthe repeating structure of Formula (II):

wherein L, X¹, X², y1, and y2 are defined as above; and A¹ is a linkinggroup selected from:

wherein R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and

wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀ alkyl,C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.

Monomers

In another aspect the present invention provides diphenolic monomershaving the following generic structure of Formula (III):

wherein L, X¹ and X², y1 and y2 are defined as above. Such monomers areuseful for making polymers that comprise repeating structural units ofFormula (I) as described in greater detail below.

A first particular aspect this invention provides diphenolic monomersderived from hydroxyalkylphenol having a generic structure of Formula(IV):

wherein R¹ is defined as above. R¹ is preferably C₁-C₁₂ alkylene, e.g.,a C₁-C₄ alkylene. More preferably R¹ is ethylene (—CH₂CH₂−).

In a preferred example according Formula (IV), R¹ is ethylene(—CH₂CH₂—), and the hydroxyalkylphenol is 4-(2-hydroxyethyl)phenol or2-(4-hydroxyphenyl)ethanol (or “tyrosol”) having the following structure(Formula (IVa):

which is a natural product present in olive oil and white wine and hasbeen shown to have both antioxidant and cardio-protective properties.The phenyl ring of tyrosol can be halogenated, and those skilled in theart will understand that teachings herein regarding tyrosol can beapplied to such halogenated forms as well.

Tyrosol can be converted into a diphenolic monomer, e.g., a diphenolicester, in several ways. It can be esterified with desaminotyrosine(DAT), with 4-hydroxybenzoic acid (HBA) or an isomer thereof, or withN-protected tyrosine to form a diphenolic monomer with an ester linkage.It can also be esterified with 0.5 mole equivalents of dicarboxylicacids to provide a family of diphenolic diester monomers that can beintroduced into polymers to control chain flexibility, as needed. Thoseskilled in the art will appreciate that use of ring halogenatedcompounds (e.g., halogenated tyrosol, halogenated DAT, etc.) results inthe corresponding halogenated polymers.

In a second particular aspect this invention provides diphenolicmonomers derived from a hydroxy-arylcarboxylic acid, having a genericstructure of Formula (IVb):

wherein R¹ is defined as above. R¹ is preferably a bond, or C₁-C₁₂alkylene, e.g., a C₁-C₄ alkylene.

In a preferred example according Formula (IVb), R¹ is a bond, and thehydroxy-arylcarboxylic acid is 4-hydroxybenzoic acid or parahydroxybenzoic acid or an isomer thereof (see Definitions Section forHBA, below), having the following structure (Formula (IVc):

4-Hydroxybenzoic acid, which does not have a chiral center, can be foundnaturally in food sources, such as in wine, in vanilla, and inunfiltered or cloudy olive oil.

Thus, in one preferred embodiment the present invention provides a newclass of diphenolic monomers of the Formula (V):

wherein L¹ is a bond, oxygen (—O—) or —R⁴—C(O)—O—, L4 is a bond, oxygen(—O—) or optionally substituted phenoxy (—C₆H₄—O—), m and n are eachindependently integers in the range of zero to 12, and X¹, X², y1, y2and R⁴ are as defined above. In an embodiment, R⁴ is selected fromsaturated and unsaturated, substituted and unsubstituted, alkylene andalkylarylene groups containing up to 18 carbon atoms. In anotherembodiment, m and n are each independently 0, 1 or 2. For example, anembodiment provides a monomer of the Formula (Va):

wherein L¹, X¹, X², y1, and y2 are as defined above.

Such monomers can be made from optionally halogenated tyrosol asdescribed in greater detail below.

In a particular exemplary embodiment according to Formula (V), L¹ and L⁴are each a bond; m is 2; n is 0; and X¹, X², y1, and y2 are as definedabove, so that the described diphenolic monomer is:

The US Published Patent Applicartion No. 2013/0203713 describes methodsof reacting iodinated phenolic species to produce a combined diphenolicmonomer having the same overall degree of iodination.

However, unlike 3,5-diodo-4-hydroxyphenylalkanoic acids, conventionalmethods for creating iodinated diphenolic monomeric species of thepresent invention through coupling of 3,5-diiodo-4-Hydroxybenzoic Acidto ethylene glycol in refluxing 1,2-dichloroethane withp-toluenesulfonic acid as catalyst are problematic owing to thediffering reactivity of the aromatic acid moiety—mostly unreactedstarting materials remain. More aggressive reaction conditions toachieve esterification, such as refluxing in toluene with a sulfuricacid catalyst, did result in more esterification but there wasconsiderable de-iodination of the ring. Similar results are expectedwith other isomers of HBA.

Therefore, a method having aspects of the invention include an initialstep of preparation of a diphenolic monomeric species in anon-halogenated state, followed by a step including substitution ofhalogen to create a respective halogenated diphenolic monomeric species,as shown in the examples herein. Advantageously, this approach permitsthe formation of an iodinated diphenolic structure under reactionconditions that would otherwise either poorly complete the esterlinkages, or de-halogenate the aromatic rings.

The non-iodinated diphenolic monomer compound ethane-1,2-diylbis(4-hydroxybenzoate) can be prepared from 4-hydroxybenzoic acid (HBA)by either of two methods, as described below. For convenience, thisdiphenolic species is abbreviated herein as HBA-EG-HBA.

In another preferred embodiment the present invention provides a classof diphenolic monomers of the Formula (VI):

wherein X¹, X², y1, y2 and Z are as defined above. For example, in anembodiment, Z is —N(R^(x))C(═O)R⁵ or —N(R^(x))COOR⁶, where R⁵, R⁶, andR^(x) are as defined above. Such monomers can be made from optionallyhalogenated 2-(4-hydroxyphenyl)ethanol (tyrosol) as described in greaterdetail below.

Further Polymers and Copolymers

The diphenolic monomers described herein, e.g., of the Formulae (III),and (V) and (VI), can be polymerized using phosgene to formpolycarbonates or with dicarboxylic acids to obtain polyarylates. Thediphenolic monomers can also be copolymerized with other diphenols (suchas desaminotyrosyl tyrosine ethyl ester) and other dihydroxyl compoundssuch as poly(ethylene glycol), polycaprolactone-diol, poly(trimethylenecarbonate), polylactide and/or polyglycolide. The polymers can be maderadio-opaque by introducing halogen, in particular iodine and/or bromineatoms, on the phenyl rings. Other optionally halogenated phenolicalcohols can be used in place of tyrosol, and other optionallyhalogenated aromatic carboxylic acids can be used in place of DAT.

Preferred biocompatible polymers that can be made using the monomersdescribed herein include those comprising a recurring structural unit ofthe following Formula (VII), (VIIa), (VIII), and/or (VIIIa):

wherein L2 is a bond or —R⁸—C(O)—, and m, n, L¹, L⁴, X¹, X², y1, y2 andR⁸ are defined above. In an embodiment, R4 (in the definition of L¹) andR⁸ (in the definition of L²) are each independently selected fromsaturated and unsaturated, substituted and unsubstituted, alkylene andalkylarylene groups containing up to 18 carbon atoms.

In Formulas (VII) and (VIII) above, in the instance where L¹ and L⁴ areboth bonds, and n=0, the hydroxy-arylcarboxylic acid on the right sideof each formula is 4-hydroxybenzoic acid or para hydroxybenzoic acid, asis likewise included in other examples above of this aspect of theinvention.

Those skilled in the art will appreciate that, depending on the mannerand extent to which the aromatic rings are substituted, the polymersdescribed herein can have various configurations. For example, thefollowing Formulae (VIIIb), (VIIIc), (VIIId), and (VIIIe) illustratevarious embodiments of a polymer containing recurring units of Formula(VIII) in which X¹ and X² are Br, y1 and y2 are 1, L¹ is O and L² is abond:

It is surprisingly discovered that replacing the amide bond with anester bond can provide a solution to one or both of the resorbabilityand processibility issues mentioned above. First, the ester bond cleaveshydrolytically to produce water-soluble fragments, thus increasing theresorption rate of the polymer. Second, reducing the number of amidehydrogens tends to lower the melt viscosity of the polymer, thusallowing facile thermal fabrication.

In another aspect, the present invention provides a polymer compositioncomprising a biocompatible polymer described herein.

In another aspect, the present invention provides a medical devicecomprising a biocompatible polymer described herein. In a preferredembodiment, the medical device is a stent.

Also provided herein is a method for making a polymer that comprises arecurring unit of Formula (I). In an embodiment, the method of makingthe polymer comprises attaching an N-substituent during the synthesis ofa corresponding monomer. In an embodiment, the method of making thepolymer comprises attaching an N-substituent during polymerization of acorresponding monomer. In an embodiment, the method of making thepolymer comprises attaching an N-substituent after polymerization of acorresponding monomer. Methods of making a polymer comprising arecurring unit of the Formula (I) are further discussed in detail below.

These and other embodiments are described in greater detail below.

DETAILED DESCRIPTION OF THE INVENTION

To meet the need of versatile moldable biodegradable and biocompatiblepolymers made using relatively nontoxic monomeric starting materials,the present application describes a variety of such monomers andpolymers prepared from these monomers.

Therefore, in one aspect the present invention provides a polymercomprising a repeating structural unit of Formula (I) in which L is—R1-A-R2- and in which A is any one of the various linking groups setforth above. Those skilled in the art will appreciate that for any ofthese “A” groups illustrated above, the depicted group is not limited tothe formula shown, when it is asymmetrical between the left and theright, but it also encompasses the corresponding mirror image of theformula, when such an arrangement would not violate known chemicalbonding principles. For example, the group denoted as

also encompasses

and the group denoted as

also encompasses

when these groups would fit into any of the Formulae described above. Asimilar principle applies to any of the formulae, or a portion thereof,described herein, when similar asymmetry exists. The disclosed formulaemerely serve as illustrations, and are not intended to be limiting.

In another aspect the present invention provides polymers, such aspolycarbonates, polyarylates, polyiminocarbonates, polyphosphazenes andpolyphosphoesters, comprising the repeating structure of Formula (II) asset forth above in which L is —R1-A-R2- and in which A and A¹ can be anycombination of any of the various linking groups defined above for A andA¹, respectively. The same principle applies to other portions orsubstituents of the various monomers and repeating structural unitsdescribed herein.

Another aspect of the present invention provides diphenolic monomersthat are capable of being polymerized to form polycarbonates orpolyarylates. The monomers provided by this aspect of the presentinvention are diphenolic compounds having the structure of Formula (III)set forth above, and in some embodiments the diphenolic monomers containtyrosine or tyrosol subunits.

In another aspect the present invention provides a polymer comprisingthe repeating structure of Formula (Ia):

wherein:

i and j are each independently zero (0) or an integer selected from 1through 6;

X¹, X², y1, and y2 are defined as above;

Q¹ and Q², at each occurrence, are each independently hydrogen, halogen,or alternatively two adjacent Q¹'s or Q²'s form a bond;

L³ is oxygen (O) or —NR^(x)—, wherein R^(x) is as defined above;

Z¹ is hydrogen, —C(O)OR⁷ or —C(O)NR^(x)R^(y), wherein R⁷, R^(x) andR^(y) are as defined above;

Z² is hydrogen, —N(R^(x))C(═O)R⁵ or —N(R^(x))COOR⁶, wherein R⁵, R⁶, andR^(x) are as defined above.

In another aspect the present invention provides a polymer comprisingthe repeating structure of Formula (IIa):

wherein i, j, y1, y2, X¹, X², Q¹, Q², Z¹, Z², L³ and A¹ is as definedabove, and k is zero or an integer from 1 through 6, inclusive.

In another aspect the present invention provides a polymer comprisingthe repeating structure of Formula (Ib):

wherein i, j, y1, y2, X¹, X², Z¹, Z², and L³ are as defined above.

In another aspect the present invention provides a polymer comprisingthe repeating structure of Formula (Iib):

wherein i, j, y1, y2, X¹, X², Z¹, Z², L³ and A¹ are as defined above.

In an embodiment, the present invention incorporates the discovery thatuseful polyarylates can be prepared from tyrosol-derived diphenolcompounds. For example, in an embodiment, the present invention providesa polymer comprising the repeating structure of Formula (IIc):

wherein i, j, y1, y2, X¹, X², Z, and A¹ are as defined above. In anembodiment, Z is hydrogen, —N(R^(x))C(═O)R⁵, or —N(R^(x))COOR⁶, whereinR⁵, R⁶, and R^(x) are as defined above.

In another aspect, the present invention provides a polymer comprisingthe repeating structure of Formula (Ic):

wherein i, j, y1, y2, X¹, X², Z¹, Z², and L³ are as defined above.

In another aspect, the present invention provides a polymer comprising arecurring unit of structure (IId):

wherein i, j, y1, y2, X¹, X², Z¹, Z², L³ and A¹ are as defined above.

In various embodiments of this aspect, A¹ is any one of the A¹ linkinggroups set forth above; i is 1 or 2; and/or j is 1 or 2.

In another aspect, the present invention provides a polymer comprising arecurring unit of structure (Id):

wherein X¹, X², y1, and y2 are defined as above. In an embodiment, X¹and X² are independently Br or I; and y1 and y2 are independently 0, 1,or 2.

The phenolic species on the right-hand portion of Formula (Id) isderived from optionally halogenated desaminotyrosine (DAT). This speciesmay be exchanged for a different hydroxy-arylcarboxylic acid, such as4-hydroxybenzoic acid (HBA) or an isomer thereof. In a preferredembodiment of this variation, where X¹′X²=iodine (particularly usefulfor conferring radiopacity), the repeating unit of Formula (Id) becomes:

Thus, the repeating unit of Formula (Ie) comprises optionallyhalogenated diphenolic ester of tyrosol and 4-hydroxybenzoic acid,permiting a polymer or copolymer of advantageous structural properties.In a particular example, y1=y2=2, providing a tetra-iodinated repeatingunit which can provide a polymer or copolymer having high radiopacity.Another embodiment is indicated by a repeating unit of Formula (IIe):

In another aspect, the present invention provides a biocompatiblepolymer composition, comprising at least a first polymer component and asecond polymer component. In one embodiment, the first polymer componentcomprises a number (n) of first recurring units of Formula (Ic) as setforth above, and the second polymer component comprises recurring unitshaving a formula selected from the group consisting of Formula (IX),Formula (X), Formula (XI), and Formula (XII):

wherein X³, X⁴, X⁵, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹² and X¹³ are independentlyselected from the group consisting of O, S and NR¹¹, where R¹¹ isselected from hydrogen and an alkyl group containing from one to 30carbon atoms;

Ar¹ and Ar² are phenylene rings optionally substituted with from one tofour substituents independently selected from the group consisting ofhalogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro,sulfoxide, and sulfonyl;

R¹² and R¹³ contain from zero to ten carbon atoms each and areindependently selected from the group consisting of a bond, optionallysubstituted alkylene, optionally substituted heteroalkylene, optionallysubstituted alkenylene, and optionally substituted heteroalkenylene;

The variables g and h in Formula (XII) are each independently integersin the range of about 1 to about 500; and

D and D¹ contain up to 24 carbon atoms and are independently selectedfrom the group consisting of optionally substituted alkylene, optionallysubstituted heteroalkylene, optionally substituted alkenylene andoptionally substituted heteroalkenylene;

or D, X⁸ and X⁹ in Formula (IX) are selected so that the intermediateHX⁸-D-X⁹H defines a hydroxyl endcapped macromer, a mercapto endcappedmacromer or an amino endcapped macromer;

or D¹, X³ and X⁴ in Formula (XI) are selected so that the intermediateHX³-D¹-X⁴H defines a hydroxyl endcapped macromer, a mercapto endcappedmacromer or an amino endcapped macromer.

In a preferred embodiment of this aspect, the first polymer componentcomprises a recurring unit of Formula (Id) as set forth above.

Copolymers

In other aspects, the present invention provides copolymers thatcomprise any two or more of the recurring units described herein. Forexample, in an embodiment, the polymer comprises two or more recurringunits selected from the group of recurring units represented by Formula(I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formual(Ie), Formula (II), Formula (IIb), Formula (IIc), Formula (IId), Formula(IIe), Formula (VII), Formula (VIII), Formula (VIIIa), Formula (VIIIb),Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (IX), Formula(X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula(XV), Formula (XVIa), Formula (XVIb), and Formula (XVIc).

In another embodiment, the polymer comprises at least two recurringunits resulting from the polymerization of any two or more monomersdescribed herein. For example, in an embodiment, the polymer comprisestwo or more recurring units resulting from copolymerization of two ormore monomers selected from the group of monomers represented by Formula(III), Formula (IV), Formula (IVa) (tyrosol), Formula (V), Formula (VI),tyrosine ethyl ester (TE), mono-iodinated TE (ITE), di-iodinated TE(I2TE), desaminotyrosine (DAT), mono-iodinated DAT (IDAT), di-iodinatedDAT (I2DAT), HBA (i.e., 4-hydroxybenzoic acid), mono-iodinated HBA,di-iodinated HBA; desaminotyrosyl tyrosine ethyl ester (DTE),mono-iodinated DTE (IDTE), di-iodinated DTE (I2DTE), N-desaminotyrosylmono-iodinated tyrosine ethyl ester (DITE), and N-desaminotyrosyldi-iodinated tyrosine ethyl ester (DI2TE). Particularly preferredrecurring units include HBA, mono-iodinated HBA, and di-iodinated HBA.

For example, an embodiment provides a polymer that contains recurringunits of the Formula (II) in which L is —R1-A-R2-, R1 and R2 are—(CH₂)₂—, A is

and A¹ is

as represented by the following Formula (XIII):

In an embodiment, the polymer is a copolymer that contains tyrosolrecurring units and recurring units of the Formula (II). An example of acopolymer containing such recurring units is represented by thefollowing Formulae (XIIIa) and XIIIb):

In an embodiment, the polymer is characterized by Formula (XIIIc):

In further examples, the structures shown in Formulas (XIII), (XIIIb),and (XIIIc) may be construed having an moiety of HBA (e.g.,4-hydroxybenzoic acid) substituted for the desaminotyrosine (DAT) moietyin one or more instances in each such Formula, shown below as FormulasDAT (XIIId), (XIIIe), and (XIIIf) repectively:

In one embodiment, the polymer including an HBA moieity is characterizedby the Formula:

In another embodiment, the polymer is characterized by the Formula:

Those skilled in the art will appreciate that polymers containing therecurring units of Formulae (XIIIa) and (XIIIb) contain a tyrosolrecurring unit and a recurring unit of Formula (II) in which L is—R1-A-R2-, R1 and R2 are —(CH₂)₂—, A is

and A¹ is

Those skilled in the art will also appreciate that, for Formula (XIIIb),X¹ and X² are I, y1 and y2 are 2, and R^(4a) is —(CH₂)₃—.

Those skilled in the art will also appreciate that the two recurringunits in Formulae (XIIIa) and (XIIIb) can appear in a polymer moleculein a variety of possible arrangements. Using Formula (XIIIb) toillustrate, without intending to be bound by theory, depending onpolymerization reaction conditions, the PrD-di I2DAT carbonate andtyrosol carbonate recurring units can be arranged in any order. That is,two adjacent units could include “PrD-diI2DAT-PrD-diI2DAT”,“PrD-diI2DAT-tyrosol”, or “tyrosol-tyrosol”.

Given the unsymmetrical structure of tyrosol, it can be connected with aPrD-diI2DAT unit using either its “head” (i.e., “phenoxy” moiety) or“tail” (i.e., the “ethylenoxy” moiety). Any two adjacent units formedfrom tyrosol itself can be in any of the “head-head”, “head-tail” and“tail-tail” arrangements. Formula (XIIIb) is repeated below (“head-tail”example), followed by a Formunla (XIIIb′), depicting a head-headexample:

In particular, when the polymerization reaction is conducted in a manneras described in Example 12, where triphosgene is added to a mixture ofPrD-diI2DAT and tyrosol, the poly(PrD-diI2DAT-co-tyrosol carbonate)product is composed of mainly polymer molecules having randomly-orderedPrD-diI2DAT and tyrosol recurring units connected through carbonate(—OC(O)O—) linkers. Unless specifically described otherwise, anyrecurring units designated as -[A]-[B]-, such as Formulae (XIIIa) and(XIIIb) above and Formulae (XVIa), (XVIb) and (XVIc) below, encompassall possible such arrangements as hereby explained.

In another comparable example, diphenolic monomers includingdi-iodinated HBA are arranged in both “head-head” and “head-tail”carbonate polymer arrangement with tyrosine moieties below:

In other aspects of the invention, the polymer comprises a backbonewhich is not naturally occurring. Alternatively and/or additionally, thepolymer may comprise a backbone comprising at least one amino acid oramino acid derivative, as described in the examples herein.

A polymer comprising a recurring unit as described herein can becopolymerized with any number of other recurring units. In anembodiment, a polymer comprising a recurring unit of any one or more ofFormula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id),Formula (II), Formula (IIb), Formula (IIc), Formula (IId), Formula(VII), Formula (VIII), Formula (VIIIa), Formula (VIIIb), Formula(VIIIc), Formula (VIIId), Formula (VIIIe), Formula (IX), Formula (X),Formula (XI), Formula (XII), and/or Formula (XIII), further comprises arecurring unit of the Formula (XIV):

wherein:

B in Formula (XIV) is —O—((CHR)p-O)q-;

p and q are each independently an integer in the range of from about 1to about 100; and

A¹ is as defined above, independently from any other A¹.

In preferred embodiments, Formula (XIV) includes polyethylene glycol(PEG) recurring units (R′H and p=2), polyproplyene glycol (PPO)recurring units (p=2, and two adjacent R's=H and CH3, respectively)and/or poly(trimethylene carbonate) (PTMC) recurring units (R═H, q=1,p=3 and A¹=

Various polycarbonates and polyarylates of the present invention employdiphenol compounds derived from tyrosol as a starting material. Examplesof tyrosol-derived diphenol monomer compounds suitable for the formationof polycarbonates or polyarylates have the structure depicted by Formula(III) defined as above.

The polymer is expected to hydrolyze to release the original diphenoland diacid, thus forming nontoxic degradation products, provided thatthe monomeric starting materials are nontoxic. The toxicologicalconcerns associated with polyarylates are met by using diphenols derivedfrom tyrosol and phosgene or dicarboxylic acids that are eithermetabolites or highly biocompatible compounds.

Therefore, another aspect of the present invention provides moldedarticles prepared from the polymers of the present invention.

Based on the foregoing, in certain embodiments of the biocompatiblepolymers described herein, A¹ is a carbonyl group having a structure of

wherein the carbonyl group is derived from a phosgene starting material.This method is essentially the conventional method for polymerizingdiols into polycarbonates. Suitable processes, associated catalysts andsolvents are known in the art and are taught in, for example, Schnell,Chemistry and Physics of Polycarbonates, (Interscience, New York 1964),the teachings of which are incorporated herein by reference. Othermethods adaptable for use to prepare the poly-carbonate and otherphosgene-derived polymers of the present invention are disclosed in U.S.Pat. Nos. 6,120,491 and 6,475,477 the disclosures of which areincorporated by reference.

In another embodiment of the polymers described herein, A¹ is a grouphaving the structure:

which is a recurring unit derived from a carboxylic acid startingmaterial or monomer. When the monomer used to form the polymer is adiphenol, the diphenol can be reacted with an aliphatic or aromaticdicarboxylic acid in the carbodiimide mediated process disclosed by U.S.Pat. No. 5,216,115 using 4-(dimethylamino) pyridinium-p-toluenesulfonate (DPTS) as a catalyst. The disclosure of U.S. Pat. No.5,216,115 is incorporated by reference, and particularly for the purposeof describing such polymerization methods. This process forms polymerswith —O—C(═O)—R⁸—C(═O)—O— linkages. R8 may be selected so that thedicarboxylic acids employed as starting materials are either importantnaturally-occurring metabolites or highly biocompatible compounds.Aliphatic dicarboxylic acid starting materials therefore include theintermediate dicarboxylic acids of the cellular respiration pathwayknown as the Krebs Cycle. The dicarboxylic acids include α-ketoglutaricacid, succinic acid, fumaric acid and oxaloacetic acid (R⁸ may be—CH₂—CH₂—C(═O)—, —CH₂—CH₂—, —CH═CH— and —CH₂—C(═O)—, respectively).

Yet another naturally occurring aliphatic dicarboxylic acid is adipicacid (R⁸ is —(CH₂)₄—), found in beet juice. Still another biocompatiblealiphatic dicarboxylic acid is sebacic acid (R⁸ is —(CH₂)₈—), which hasbeen studied extensively and has been found to be nontoxic as part ofthe clinical evaluation of poly(bis(p-carboxyphenoxy)propane-co-sebacicacid anhydride) by Laurencin et al., J. Biomed. Mater. Res., 24, 1463-81(1990).

Other biocompatible aliphatic dicarboxylic acids include oxalic acid (R⁸is a bond), malonic acid (R⁸ is —CH₂—), glutaric acid (R⁸ is —(CH₂)₃—),pimelic acid (R⁸ is —(CH₂)₅—), suberic acid (R⁸ is —(CH₂)₆—), andazelaic acid (R⁸ is —(CH₂)₇—). R⁸ can thus represent —(CH₂)_(n)—, wheren is between 0 and 8, inclusive. Among the suitable aromaticdicarboxylic acids are terephthalic acid, isophthalic acid andbis(p-carboxy-phenoxy) alkanes such as bis(p-carboxy-phenoxy) propane.

Preferred polymers comprise a recurring unit as described herein, e.g.,a recurring unit selected from the group of recurring units representedby Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id),Formula (Ie), Formula (II), Formula (IIb), Formula (IIc), Formula (IId),Formula (IIe), Formula (VII), Formula (VIII), Formula (VIIIa), Formula(VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula(IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula(XIV), Formula (XV), Formula (XVIa), Formula (XVIb), and Formula (XVIc).Preferred polymers can contain combinations of derivatives of structuralunits selected from dicarboxylic acids, halogenated (e.g., iodinated orbrominated) derivatives of desaminotyrosyl-tyrosine and poly(alkyleneglycols), which exhibit desirable physicomechanical and physicochemicalproperties that are consistent with their use in fabrication of medicaldevices, including stents. For example, the stents described inaccordance with preferred embodiments of the present invention: (a) aresufficiently radiopaque to be visible by conventional X-ray fluoroscopy;(b) are of sufficient strength to support medically relevant levels ofradial compression within an artery or surrounding tissue; and/or (c)have a desirable resorption profile that may be adjusted to account forthe needs of a range of applications requiring the presence of a stentfor different lengths of time or for the elution of therapeutics.

For example, in accordance with one preferred embodiment of the presentinvention, a medical device is disclosed, comprising an inherentlyradiopaque, biocompatible, bioresorbable polymer, including homogeneouspolymers, copolymers and blends thereof, wherein the polymer comprisesone or more recurring units of the Formula (XV):

wherein:

X¹, X², y1, y2, L, B, and A¹ are each independently as defined above;and

a, b and c may range from 0 to 1, with a normalized sum a+b+c=1.

Preferably, X¹, X², y1, and y2 in Formula (XV) are selected so that X¹and X² are present in an amount that is effective to render the polymerradiopaque. For example, in an embodiment, the sum of y1 and y2 inFormula (XV) is at least one. In another embodiment, B in Formula (XV)is an aliphatic linear or branched diol or a poly(alkylene glycol) unit.

Examples of preferred copolymers include those of the Formula (XVIa),(XVIb) and (XVIc), as follows:

In each of particular examples shown in Formulas (XVIa), (XVIb) and(XVIc) above, the halogenated moiety in each case comprisesdesaminotyrosine (DAT). Halogenation of the aromatic rings may beaccomplished as described in the examples below, and by conventionalmethods as detailed in U.S. Pat. No. 6,475,477; herein incorporated inits entirety by reference and particularly for the purpose of describingmethods of halogenating monomers. Preferred polymers are sufficientlyhalogenated to render the resulting polymers radiopaque, e.g., y1 and y2in any of the formulas described herein may independently be 0, 1, 2, 3or 4. Halogenation of aromatic rings is preferred. In an embodiment, thesum of y1 and y2 is at least one. Various other groups within thepolymer may also be halogenated, e.g., tyrosol moieties.

Aspects of the inventions herein include examples whereby in any or allof Formulas (XVIa), (XVIb) and (XVIc) above, one or more of thedesaminotyrosine (DAT) groups may be replaced by anotherhydroxy-arylcarboxylic acid, such as 4-hydroxybenzoic acid (HBA) or anisomer thereof. In the case of halogenated HBA, an alternative scheme ofhalogenation may be employed, as is described above.

It has been surprisingly discovered that after replacement of an amidebond in a recurring unit with an ester bond, which would be expected toreduce inter-chain hydrogen bonding, in various embodiments theresulting polymer has a higher glass temperature and meltingtemperature. It was also unexpected that various polymers prepared fromtyrosol-derived monomers were observed to be semi-crystalline and topossess mechanical strength suitable for high strength applications.

Other Preferred Embodiments

One aspect of the invention is directed to a biocompatible polymercomprising a recurring unit of Formula (XVIII):

where:

j and k are each independently zero or an integer selected from 1 to 6,provided that j and k are not both 0;

X¹ and X² are each independently bromine (Br) or iodine (I), and y1 andy2 are each independently 0, 1, 2, 3, or 4;

L¹ is selected from the group consisting of oxygen (—O—), —R⁴—C(═O)—O—,and —O—R^(4a)—O—C(═O)—; wherein R⁴ is selected from the group consistingof C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀alkynylarylene, and C₂-C₃₀ heteroarylene; and R^(4a) is selected fromthe group consisting of C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;

L⁴ is selected from the group consisting of a bond, and optionallysubstituted phenoxy (—C₆H₄—O—);

L⁵ is selected from the group consisting of a bond and —CH₂—;

Q² at each occurrence is independently hydrogen or halogen; or twoadjacent Q² form a double bond when adjacent Qs are present; or Z² andan adjacent Q² form a double bond;

Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶, —C(O)OR⁷ or—C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a double bond;

wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at each occurrenceselected from the group consisting of hydrogen, alkyl, aryl, alkylaryl,arylalkyl, heteroalkyl, and heteroalkylaryl, wherein the non-hydrogengroups contain up to 30 carbon atoms, wherein the heteroalkyl groupcontains from 1 to 10 heteroatoms independently selected from O, N andS, and the heteroalkylaryl group contains from 1 to 3 heteroatomsindependently selected from O, N and S; and

wherein A¹ is selected from the group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and

wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀ alkyl,C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.

In one embodiment of the biocompatible polymer L¹ is oxygen and L⁴ is abond, providing a recurring unit of Formula (XVIIIa):

In one embodiment of the biocompatible polymer L¹ is oxygen and L⁴ is abond, and Q2 is hydrogen, providing a recurring unit of Formula(XVIIIb):

In one embodiment of the biocompatible polymer L⁵ is a bond, providing arecurring unit of Formula (XVIIIc):

In one embodiment of the biocompatible polymer j=k=1, L1 is oxygen, L4and L⁵ are each a bond, and Q² and Z² are each hydrogen, providing arecurring unit of Formula (XVIIId):

One embodiment of the biocompatible polymer comprising a recurring unitof Formula (XVIII) further comprises a tyrosol recurring unit and ischaracterized by the Formula (XVIIIe):

One embodiment of the biocompatible polymer comprising a recurring unitof Formula (XVIII) further comprises a tyrosol recurring unit and ischaracterized by the Formula (XVIIIf):

One embodiment of the biocompatible polymer comprising a recurring unitof Formula (XVIII) further comprises a p-hydroxybenzoyl tyrosolrecurring unit and is characterized by the Formula (XVIIIg):

One embodiment of the biocompatible polymer comprising a recurring unitof Formula (XVIII) further comprises an α-hydroxyacid recurring unit andis characterized by the Formula (XVIIIh):

where R¹⁵═H or CH₃, and r=1 to about 300.

One embodiment of the biocompatible polymer comprising a recurring unitof Formula (XVIII) further comprises an iodinated tyrosol recurring unitand is characterized by the Formula (XVIIIi):

A related aspect of the invention is directed to a biocompatible polymercomprising a recurring unit of Formula (XIX):

where

j and k are each independently zero or an integer selected from 1 to 6,provided that j and k are not both 0;

X¹ and X² are each independently bromine (Br) or iodine (I), and y1 andy2 are each independently 0, 1, 2, 3, or 4;

L¹ is selected from the group consisting of oxygen (—O—), —R⁴—C(═O)—O—,and —O—R^(4a)—O—C(═O)—; wherein ^(R4) is selected from the groupconsisting of C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene,C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀ heteroalkynylene,C₆-C₃₀ arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀alkynylarylene, and C₂-C₃₀ heteroarylene; and R^(4a) is selected fromthe group consisting of C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;

L⁴ is selected from a bond, and optionally substituted phenoxy(—C₆H₄—O—);

L⁵ is selected from a bond and —CH₂—;

Q² at each occurrence is independently hydrogen or halogen; or twoadjacent Q² form a double bond when adjacent Qs are present; or Z² andan adjacent Q² form a double bond;

Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶, —C(O)OR⁷ or—C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a double bond; and

wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at each occurrenceselected from the group consisting of hydrogen, alkyl, aryl, alkylaryl,arylalkyl, heteroalkyl, and heteroalkylaryl, wherein the non-hydrogengroups contain up to 30 carbon atoms, wherein the heteroalkyl groupcontains from 1 to 10 heteroatoms independently selected from O, N andS, and the heteroalkylaryl group contains from 1 to 3 heteroatomsindependently selected from O, N and S.

In one embodiment of the biocompatible polymer L¹ is oxygen and L⁴ is abond, providing a recurring unit of Formula (XIXa):

In one embodiment of the biocompatible polymer L¹ is oxygen and L⁴ is abond, and Q² is hydrogen, providing a recurring unit of Formula (XIXb):

In one embodiment of the biocompatible polymer L⁵ is a bond, providing arecurring unit of Formula (XIXc):

In one embodiment of the biocompatible polymer j=k=1, L¹ is oxygen, L⁴and L⁵ are each a bond, and Q² and Z² are each hydrogen, providing arecurring unit of Formula (XIXd):

In some embodiments of the above polymers which comprise recurring unitsof Formulae (XVIII), (XVIIIa-i), (XIX) and (XIXa-d) the phenyl groups ofthe recurring unit have the phenolic oxygens in the para-position. Insome embodiments of the polymers comprising recurring units of Formulae(XVIII), (XVIIIa-i), (XIX) and (XIXa-d) L⁴ is a bond, L¹ is oxygen, andQ² and Z² are both hydrogen. In some embodiments of the polymerscomprising recurring units of Formulae (XVIII), (XVIIIa-i), (XIX) and(XIXa-d) X¹ and X² are iodine, and at least one of y1 and y2 isnon-zero. In some embodiments of the polymers comprising recurring unitsof Formulae (XVIII), (XVIIIa-i), (XIX) and (XIXa-d) X¹ and X² areiodine, at least one of y1 and y2 is 2, and the phenyl groups of therecurring unit have the phenolic oxygens in the para-position.

In some embodiments of the polymers comprising recurring units ofFormulae (XVIII), (XVIIIa-i), (XIX) and (XIXa-d), the polymer is apolycarbonate and further comprises a recurring unit of optionallyiodinated tyrosol.

In some embodiments, any of the above-described biocompatible copolymersfurther comprise a tyrosol recurring unit of the formula:

wherein A¹ is selected from the group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀alkyl, C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.In some embodiments, any of theabove-described biocompatible copolymers further comprise a recurringunit of the formula:

wherein R¹⁵ is H or CH₃, r is 1 to about 300, and A¹ is as describedabove.

In some embodiments, any of the above-described biocompatible copolymersis characterized as being a block copolymer with a macromer of theformula:

wherein B is —O—((CH₂)_(p)—O)_(q)— or —O—(CH₂CH(CH₃)—O)_(q)—;

p is an integer ranging from 1 to about 6, and q is about 5 to about3000; and

A¹ is as described above.

In some embodiments, any of the above-described biocompatible copolymersfurther comprise a p-hydroxybenzoate recurring unit of the formula:

wherein X¹ is selected from Br and I and y1=0, 1 or 2.

Another aspect of the invention is directed to a biocompatiblepolyurethane comprising an optionally iodinated tyrosine or anoptionally iodinated tyrosine ester recurring unit, and a secondrecurring unit selected from the group consisting of HBA (hydroxybenzoidacid), mono-iodinated HBA and di-iodinated HBA.

Another aspect of the invention is directed to a diphenol monomercompound having the Formula (XX):

where:

j and k are each independently zero or an integer selected from 1 to 6,provided that j and k are not both 0;

X¹ and X² are each independently bromine (Br) or iodine (I), and y¹ andy² are each independently 0, 1, 2, 3, or 4;

L¹ is selected from oxygen (—O—), —R⁴—C(═O)—O—, and —O—R^(4a)—O—C(═O)—;wherein R⁴ is selected from the group consisting of C₁-C₃₀ alkylene,C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene; and R^(4a) is selected from C₁-C₃₀ alkylene, C₂-C₃₀alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene;

L⁴ is selected from a bond, and optionally substituted phenoxy(—C₆H₄—O—);

L⁵ is selected from a bond and —CH₂—;

Q² at each occurrence is independently hydrogen or halogen; or twoadjacent Q² form a double bond when adjacent Qs are present; or Z² andan adjacent Q² form a double bond;

Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶, —C(O)OR⁷ or—C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a double bond; and

wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at each occurrenceselected from the group consisting of hydrogen, alkyl, aryl, alkylaryl,arylalkyl, heteroalkyl, and heteroalkylaryl, wherein the non-hydrogengroups contain up to 30 carbon atoms, wherein the heteroalkyl groupcontains from 1 to 10 heteroatoms independently selected from O, N andS, and the heteroalkylaryl group contains from 1 to 3 heteroatomsindependently selected from O, N and S.

In one embodiment of the diphenol compound the phenolic hydroxy groupsare in the para-position, providing a diphenol compound having theFormula (XXa):

In one embodiment of the diphenol compound L⁵ is a bond. In oneembodiment of the diphenol compound L⁴ and L⁵ are each a bond, L¹ isoxygen, Z² is hydrogen and Q² is hydrogen. In one embodiment of thediphenol compound L⁴ and L⁵ are each a bond, L¹ is oxygen, Z² ishydrogen, Q² is hydrogen and k=j=1. In one embodiment of the diphenolcompound L⁴ and L⁵ are each a bond, L¹ is oxygen, Q² and Z² are bothhydrogen, k=j=1, X¹ and X² are iodine, and at least one of y1 and y2 isnon-zero.

Polymer compositions can be prepared comprising any of theabove-described the biocompatible polymers and at least onepharmaceutically acceptable carrier, additive or excipient. In someembodiments the polymer compositions comprise polymers containing one ormore of the recurring units of Formulae (XVIII), (XVIIIa-i), (XIX) and(XIXa-d).

Medical devices can be fabricated from any of the above-describedbiocompatible polymers. In some embodiments the medical device comprisesa biocompatible polymer containing one or more of the recurring units ofFormulae (XVIII), (XVIIIa-i), (XIX) and (XIXa-d). The medical device canfurther comprise a biologically active compound incorporated into thebiocompatible polymer. In some embodiments the biologically activecompound can be selected from the group consisting of chemotherapeuticagents, non-steroidal anti-inflammatory agents, steroidalanti-inflammatory agents, and wound healing agents. In certainembodiments the medical device is a stent. Preferably the stentcomprises any one or more of the biocompatible polymers described above;and particularly of one or more of the biocompatible polymers comprisingone or more of the recurring units of Formulae (XVIII), (XVIIIa-i),(XIX) and (XIXa-d).

Monomer and Polymer Syntheses

The polymers described herein (including, e.g, polymers comprising arecurring unit selected from the group of recurring units represented byFormula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id),Formula (Ie), Formula (II), Formula (IIb), Formula (IIc), Formula (IId),Formula (IIe), Formula (VII), Formula (VIII), Formula (VIIIa), Formula(VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula(IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula(XIV), Formula (XV), Formula (XVIa), Formula (XVIb), Formula (XVIc),Formula (XVIII), Formulae (XVIIIa-i), Formula (XIX) and Formulae(XIXa-d) may be synthesized by various conventional reactions known inthe art.

For example, the diphenolic monomer compounds can be reacted withaliphatic or aromatic dicarboxylic acids in a carbodiimide-mediateddirect polyesterification using DPTS as a catalyst to form aliphatic oraromatic polyarylates. Examples of dicarboxylic acids suitable forpolymerization to form polyarylates have a structure of Formula (XVII):

in which, for the aliphatic polyarylates, R¹⁴ is selected from saturatedand unsaturated, substituted and unsubstituted alkylene or alkylarylenegroups containing up to 18 carbon atoms, and preferably from 2 to 12carbon atoms. For the aromatic polyarylates, R¹⁴ is selected fromarylene groups containing up to 18 carbon atoms and preferably from 6 to12 carbon atoms. In some embodiments, R¹⁴ is defined as above for R⁸.

R¹⁴ is preferably selected so that the dicarboxylic acids employed asstarting materials are either important naturally-occurring metabolitesor highly biocompatible compounds. Examples of preferred aliphaticdicarboxylic acid starting materials are described elsewherein herein.

The polyarylates can also be prepared by the method disclosed by Higashiet al., J. Polym. Sci.: Polym. Chem. Ed., 21, 3233-9 (1983) usingarylsulfonyl chloride as the condensing agent, by the process of Higashiet al., J. Polym. Sci.: Polym. Chem. Ed., 21, 3241-7 (1983) usingdiphenyl chlorophosphate as the condensing agent, by the process ofHigashi et al., J. Polym. Sci.: Polym. Chem. Ed., 24, 97-102 (1986)using thionyl chloride with pyridine as the condensing agent, or by theprocess of Elias, et al., Makromol. Chem., 182, 681-6 (1981) usingthionyl chloride with triethylamine A preferred polyesterificationprocedure is the method disclosed by Moore et al., Macromol., 23, 65-70(1990) utilizing carbodiimide coupling reagents as the condensing agentswith the specially designed catalyst DPTS.

A particularly preferred polyesterification technique modifies themethod of Moore to utilize an excess of the carbodiimide couplingreagent. This technique tends to produce aliphatic polyarylates havingmolecular weights greater than those obtained by Moore. Essentially anycarbodiimide commonly used as a coupling reagent in peptide chemistrycan be used as a condensing agent in the preferred polyesterificationprocess. Such carbodiimides are well-known and disclosed in Bodanszky,Practice of Peptide Synthesis (Springer-Verlag, New York, 1984) andinclude dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride,N-cyclohexyl-N′-(2′-morpholinoethyl)carbodiimide-metho-p-toluenesulfonate, N-benzyl-N′-3′-dimethyl-aminopropyl-carbodiimidehydrochloride, 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimidemethiodide, N-ethylcarbodiimide hydrochloride, and the like. Thepreferred carbodiimides are dicyclohexyl carbodiimide anddiisopropylcarbodiimide.

An esterification reaction mixture can generally be formed by contactingexactly equimolar quantities of the diphenol and the dicarboxylic acidin a solvent for the diphenol and the dicarboxylic acid. Suitablesolvents include methylene chloride, tetrahydrofuran, dimethylformamide,chloroform, carbon tetrachloride and N-methyl pyrrolidinone. It is notnecessary to bring all reagents into complete solution prior toinitiating the polyesterification reaction, although the polymerizationof slightly soluble monomers such as desaminotyrosyltyrosine ethyl esterand succinic acid will typically yield higher molecular weight polymerswhen the amount of solvent is increased. The reaction mixture can alsobe heated gently to aid in the partial dissolution of the reactants.

The polyarylates can be worked up and isolated by known methods commonlyemployed in the field of synthetic polymers to produce a variety ofuseful articles with valuable physical and chemical properties, allderived from tissue compatible monomers. The useful articles can beshaped by conventional polymer-forming techniques such as extrusion,compression molding, injection molding, and the like. Molded articlesprepared from the polyarylates are useful, inter alia, as degradablebiomaterials for medical implant applications. Such applications includethe use of the molded articles as vascular grafts and stents, boneplates, sutures, implantable sensors, barriers for surgical adhesionprevention, implantable drug delivery devices and other therapeutic aidsand articles which decompose harmlessly within a known period of time.

Synthetic Schemes 1-4 illustrate the preparation of various types ofphenolic monomers useful for the making polymers containing recurringunits of the Formula (I). One of ordinary skill in the art, guided bythe disclosure herein, would understand that these synthetic schemes maybe readily adapted to prepare phenolic monomers containing pendant sidechains such as —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶, —COOR⁷ and/or—CONR^(x)R^(y), as defined above.

As would be understood by those skilled in the art, a reaction betweentyrosol or analogue with phosgene or triphosgene, as illustrated inScheme 3, would likely give a mixture of three types of dimers linked bya carbonate (—OC(O)O—) group (i.e., “head-head”, “tail-tail” and“head-tail”) and/or the corresponding polymers, depending on thereaction conditions employed. Therefore, in some embodiments, thepresent invention provides preparation of these specific dimers andpolymers under controlled conditions, as illustrated in Example 17.

In synthetic Schemes 1-10, X¹, X², y1, y2, R⁴, R^(4a) and R⁸ are asdefined above. In various embodiments of the monomers and polymersdescribed herein, R⁴, R^(4a) and R⁸ are each independently C₁-C₃₀ alkyl,e.g., C₁-C₆ alkyl, C₁-C₈ alkyl, C₁-C₁₀ alkyl, etc. Those skilled in theart will appreciate the extent to which variables (e.g., X¹ and X², andy1 and y2, respectively) may be used interchangeably in the variousformulae and schemes provided herein when the depicted structures aresymmetrical. Thus, X¹ (and X²) may be a halogen, which at eachoccurrence independently may be selected from iodo, bromo, chloro, andfluoro. Preferably, the halogen is iodo or bromo. Halogenation may beperformed by conventional reactions known in the art. For instance,iodination may be performed on aryl rings by treatment with KI, ICl, IF,benzyltrimethylammonium dichloroiodate, or I₂ in the presence of coppersalts. Similarly, bromination may be performed on aryl rings bytreatment with bromine in the presence of a catalyst, such as iron.Other brominating reagents include HOBr and bromo amides. The abovesynthetic schemes are simplified for illustration purpose. Many variantscan be obtained using similar synthetic strategies known to a person ofskill in the art, for example, in Scheme 5:

The coupling of the acid and the alcohol may also be performed byconventional reactions known in the art. Standard coupling reagents,including EDCI, HBTU, HOBt, and the like, may be used for activation ofthe reactants. Examples of synthesis of these polymers are illustratedin the following synthetic Schemes 6-9:

In some embodiments the polymers described herein contain phosphorus.The versatility of these polymers may come from the versatility of thephosphorus atom, which is known for a multiplicity of reactions. Itsbonding may involve the 3p orbitals or various 3s-3p hybrids; spdhybrids are also possible because of the accessible of orbitals. Thus,the physico-chemical properties of the poly(phosphoesters) may bereadily changed by varying either the R or R′ group. Thebiodegradability of the polymer is due primarily to the physiologicallylabile phosphoester bond in the backbone of the polymer. By manipulatingthe backbone or the sidechain, a wide range of biodegradation rates areattainable.

As those skilled in the art would appreciate, when a monomer has anunsymmetrical structure having two equally or similarly reactivefunctional groups for polymerization, the polymers formed would largelycontain the monomeric units in random orders. Such examples include, butare not limited to, the polymerization reactions illustrated in Schemes6-9 above.

Synthetic Schemes 10-11 below illustrate the syntheses ofpoly(phosphonates) and poly(phosphates), respectively.

In Schemes 10-13, X is Cl or Br, and X¹, X², y1, y2, L, R⁹ and R¹⁰ areas defined above. For example, poly(phosphates) may be prepared by adehydrochlorination between a phosphodichloridate and a diol accordingto the following synthetic Scheme 12:

Poly(phosphonates) may be prepared by a similar condensation betweenappropriately substituted dichlorides and diols.

Poly(phosphites) may be prepared from glycols in a two-step condensationreaction. A 20% molar excess of a dimethylphosphite is preferably usedto react with the glycol, followed by the removal of themethoxyphosphonyl end groups in the oligomers by high temperature. Anadvantage of melt polycondensation is that it avoids the use of solventsand large amounts of other additives, thus making purification morestraightforward. It may also provide polymers of reasonably highmolecular weight. Polymerization may also be carried out in solution. Achlorinated organic solvent may be used, such as chloroform,dichloromethane, or dichloroethane. To achieve high molecular weights,the solution polymerization is preferably run in the presence ofequimolar amounts of the reactants and, more preferably, astoichiometric amount of an acid acceptor or a Lewis acid-type catalyst.Useful acid acceptors include tertiary amines such as pyridine ortriethylamine Examples of useful Lewis acid-type catalysts includemagnesium chloride and calcium chloride. The product may be isolatedfrom the solution by precipitation in a non-solvent and purified toremove the hydrochloride salt by conventional techniques known to thoseof ordinary skill in the art, such as by washing with an aqueous acidicsolution, e.g., dilute HCl.

Halogenated phenolic monomers may also be polymerized to formpolyiminocarbonates as illustrated in synthetic Scheme 13:

Diphenolic Ester Monomers Comprising Halogenated HBA.

Unlike the example of Scheme 1, in which I2DAT is reacted with I₂TyrosolPrD-di I₂DAT to produce a quatra-iodinated diphenolic ester,conventional methods for creating iodinated diphenolic monomeric speciesthrough coupling of 3,5-diiodo-4-Hydroxybenzoic Acid (I₂HBA) areproblematic owing to the differing reactivity of the aromatic acidmoiety relative to DAT—mostly unreacted starting materials remain.

Alternatively, using more aggressive reaction conditions, such as highertemperatures, to achieve esterification of HBA, and/or refluxing intoluene with a sulfuric acid catalyst, do result in more esterificationbut there is considerable de-iodination of the ring. For this reason,Schemes 14a and 14b depict a process for producing a quatra-iodinateddiphenolic ester (or other halogen combination) via a 2-step process.

Scheme 14a shows the production of a non-halogenated diphenolic estermonomer by reaction of 4-Hydroxybenzoic Acid with tyrosol. Methods usedmay include, e.g., heating 4-hydroxybenzoic acid (HBA) together withtyrosol in 4-toluenesulfonic acid monohydrate, and 1,2-dichloroethane(DCE) under reflux. Alternative method may include Fisher synthesis.andheating with catalytic amount of sulfuric acid with toluene underreflux. The product is the tyrosol ester of 4-hydroxybenzoic acid, ortyrosyl(4-hydroxybenzoate), abbreviated herein as BTy.

Scheme 14b shows the production of halogenated enated diphenolic estermonomer by reaction of tyrosyl(4-hydroxybenzoate) to iodinate theconstituent rings of the diphenol, e.g., the reaction may be carried outin ethanol using iodine in the presence of sulfuric acid, whereinaqueous H₂O₂ or potassium iodate is used as the oxidizing agent. Theproduct is 3,5-diiodotyrosyl(4-hydroxy-3,5-diiodophenyebenzoate.

Polyiminocarbonates are structurally related to polycarbonates. Thepolyiminocarbonates have imino groups in the places typically occupiedby carbonyl oxygen in the polycarbonates. Thus, the polyiminocarbonateshave linkages according to the formula:

Inclusion of iminocarbonate linkages may impart a significant degree ofhydrolytic instability to the polymer. The polyiminocarbonates havedesirable mechanical properties akin to those of the correspondingpolycarbonates.

Starting materials described herein are available commercially, areknown, or may be prepared by methods known in the art. Additionally,starting materials not described herein are available commercially, areknown, or may be prepared by methods known in the art.

Starting materials may have the appropriate substituents to ultimatelygive desired products with the corresponding substituents.Alternatively, substituents may be added at any point of synthesis toultimately give desired products with the corresponding substituents.

The synthetic schemes illustrated herein show methods that may be usedto prepare the compounds of preferred embodiments. One skilled in theart will appreciate that a number of different synthetic reactionschemes may be used to synthesize the compounds of preferredembodiments. Further, one skilled in the art will understand that anumber of different solvents, coupling agents and reaction conditionsmay be used in the synthetic reactions to yield comparable results.

One skilled in the art will appreciate variations in the sequence and,further, will recognize variations in the appropriate reactionconditions from the analogous reactions shown or otherwise known whichmay be appropriately used in the processes above to make the compoundsof preferred embodiments.

In the processes described herein for the preparation of the compoundsof preferred embodiments, the requirements for protective groups aregenerally well recognized by one skilled in the art of organicchemistry, and accordingly the use of appropriate protecting groups isnecessarily implied by the processes of the schemes herein, althoughsuch groups may not be expressly illustrated. Introduction and removalof such suitable protecting groups are well known in the art of organicchemistry; see for example, T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley (New York), 1999.

The products of the reactions described herein can be isolated byconventional means such as extraction, distillation, chromatography, andthe like.

The salts of the compounds described herein can be prepared by reactingthe appropriate base or acid with a stoichiometric equivalent of thecompound.

In some embodiments, the polymer comprises poly(ether carbonate) wtihtyrosol-bioactive moiety. A desaminotyrosyl-tyrosine dipeptide can becombined with the PEG in methylene chloride and phosgene can be added asa solution in toluene. The reaction would be completed in around 9minutes. In some embodiments, this reaction is carried out for from 1-60minutes. In an embodiment, the polymer comprises poly(tyrosinecarbonate) pendant bioactive moiety groups. In some embodiments, thepolymer comprises poly(ether carbonate) tyrosine-diol copolymer with abioactive moiety in the backbone. In some embodiments, the polymercomprises poly(ether carbonate) tyrosine-diol copolymer with a pendantbioactive moiety. In some embodiments, the polymer comprises poly(etherester) tyrosine-bioactive moiety-diacid copolymer. In some embodiments,the polymer comprises poly(imino carbonate) tyrosine-bioactivemoiety-copoymer. In some embodiments, the polymer comprises poly(imonotyrosine) with pendant PEG groups.

In another aspect the present invention provides a medical device thatcomprises a polymer and/or polymer composition as described herein. Forexample, an embodiment provides a stent that comprises a polymercomposition as described herein. Another embodiment provides a method oftreating a body lumen, comprising deploying the stent within the bodylumen. These and other embodiments are described in greater detailbelow.

Definitions

The term “biodegradable,” as used herein, refers to a property ofpolymer whose molecular weight goes down because of hydrolysis orenzymatic reactions under physiological conditions such that the polymeris transformed into lower molecular weight oligomers in a period not toexceed four (4) years.

The term “oligomer,” as used herein, refers to a hydrolyzed product of apolymer, whose molecular weight is less than 10% of the originalpolymer.

The terms “alkyl”, “alkylene” and similar terms have the usual meaningknown to those skilled in the art and thus may be used to refer tostraight or branched hydrocarbon chain fully saturated (no double ortriple bonds) hydrocarbon group. Terminal alkyl groups, e.g., of thegeneral formula —C_(n)H_(2n+1), may be referred to herein as “alkyl”groups, whereas linking alkyl groups, e.g., of the general formula—(CH₂)_(n)—, may be referred to herein as “alkylene” groups. The alkylgroup may have 1 to 50 carbon atoms (whenever it appears herein, anumerical range such as “1 to 50” refers to each integer in the givenrange; e.g., “1 to 50 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 50 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group may also be a medium size alkyl having 1 to30 carbon atoms. The alkyl group could also be a lower alkyl having 1 to5 carbon atoms. The alkyl group of the compounds may be designated as“C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄alkyl” indicates that there are one to four carbon atoms in the alkylchain, i.e., the alkyl chain is selected from the group consisting ofmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, hexyl and the like.

The alkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is(are) one or more group(s) individually andindependently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl,(heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy,acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protectedC-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof. Wherever a substituent is described as being “optionallysubstituted” that substitutent may be substituted with one of the abovesubstituents.

An “aralkyl” is an aryl group connected, as a substituent, via analkylene group. The alkylene and aryl group of an aralkyl may besubstituted or unsubstituted. Examples include but are not limited tobenzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, andnaphtylalkyl. In some cases, the alkylene group is a lower alkylenegroup. An alkylaryl group may be substituted or unstubstituted.

As noted above, alkyl groups may link together other groups, and in thatcontext may be referred to as alkylene groups. Alkylene groups are thusbiradical tethering groups, forming bonds to connect molecular fragmentsvia their terminal carbon atoms. Examples include but are not limited tomethylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), andbutylene (—(CH₂)₄—) groups. An alkylene group may be substituted orunsubstituted.

The terms “alkenyl”, “alkenylene” and similar terms have the usualmeaning known to those skilled in the art and thus may be used to referto an alkyl or alkylene group that contains in the straight or branchedhydrocarbon chain containing one or more double bonds. An alkenyl groupmay be unsubstituted or substituted. When substituted, thesubstituent(s) may be selected from the same groups disclosed above withregard to alkyl group substitution unless otherwise indicated.

An “amide” is a chemical moiety with formula —(R)_(n)—C(O)NHR′ or—(R)_(n)—NHC(O)R′, where R and R′ are independently selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon), andwhere n is 0 or 1. An amide may be an amino acid or a peptide moleculeattached to a molecule of the present invention, thereby forming aprodrug. An “amide linkage” is an amide group (—C(O)NH—) that links twochemical moieties to one another.

Any amine, hydroxy, or carboxyl side chain on the compounds disclosedherein can be esterified or amidified. The procedures and specificgroups to be used to achieve this end are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated by reference herein inits entirety.

As used herein, “aryl” refers to a carbocyclic (all carbon) ring or twoor more fused rings (rings that share two adjacent carbon atoms) thathave a fully delocalized pi-electron system. Examples of aryl groupsinclude, but are not limited to, benzene, naphthalene and azulene. Anaryl group may be substituted or unsubstituted. When substituted,hydrogen atoms are replaced by substituent group(s) that is(are) one ormore group(s) independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, hetero-aryl,heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl,hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalo-methanesulfonamido, and amino, including mono- anddi-substituted amino groups, and the protected derivatives thereof. Whensubstituted, substituents on an aryl group may form a non-aromatic ringfused to the aryl group, including a cycloalkyl, cycloalkenyl,cycloalkynyl, and heterocyclyl.

As used herein, “heteroalkyl” refers to an alkyl group where one or morecarbon atoms has been replaced with a heteroatom, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur.

The terms “heteroalkyl”, “heteroalkylene,” and similar terms have theusual meaning known to those skilled in the art and thus may be used torefer to an alkyl group or alkylene group as described herein in whichone or more of the carbons atoms in the backbone of alkyl group oralkylene group has been replaced by a heteroatom such as nitrogen,sulfur and/or oxygen. Likewise, the term “heteroalkenylene” may be usedto refer to an alkenyl or alkenylene group in which one or more of thecarbons atoms in the backbone of alkyl group or alkylene group has beenreplaced by a heteroatom such as nitrogen, sulfur and/or oxygen.

As used herein, “heteroaryl” refers to an aryl group where one or morecarbon atoms has been replaced with a heteroatom, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur.

For convenience and conciseness, sometimes the terms “alkyl”, “alkenyl”,“alkynyl”, “aryl”, “heteroaryl”, and “alkylaryl”, or the like, may beused to refer to the corresponding linking groups when they serve toconnect two moieties of a molecule, either monomeric or polymeric, whichis readily understood by those skilled in the art. That is, on suchoccasions “alkyl” should be interpreted as “alkylene”; “alkenyl” shouldbe interpreted as “alkenylene”; “aryl” should be interpreted as“arylene”; and so on.

A “heavy atom” is an atom that, when attached to a polymer, renders thepolymer easier to detect by an imaging technique as compared to apolymer that does not contain the heavy atom. Since many polymerscontain relatively low atomic number atoms such as hydrogen, carbon,nitrogen, oxygen, silicon and sulfur, in most cases heavy atoms have anatomic number of 17 or greater. Preferred heavy atoms have an atomicnumber of 35 or greater and include bromine, iodine, bismuth, gold,platinum tantalum, tungsten and barium.

A “hydrocarbon” is an organic compound consisting entirely of hydrogenand carbon. Examples of hydrocarbons include unsubstituted alkyl groups,unsubstituted aryl groups, and unsubstituted alkylaryl groups. Anysubstitution to an alkyl group, aryl group, or alkylaryl group in ahydrocarbon would only comprise carbon and/or hydrogen atoms.

As used herein, the terms “macromer”, “macromeric” and similar termshave the usual meaning known to those skilled in the art and thus may beused to refer to oligomeric and polymeric materials that arefunctionalized with end groups that are selected so that the macromerscan be copolymerized with other macromers or monomers. A wide variety ofmacromers and methods for making them are known to those skilled in theart. Examples of suitable macromers include hydroxy endcapped polylacticacid macromers, hydroxy endcapped polyglycolic acid macromers, hydroxyendcapped poly(lactic acid-co-glycolic acid) macromers, hydroxyendcapped polycaprolactone macromers, poly(alkylene diol) macromers,hydroxy end-capped poly(alkylene oxide) macromers and hydroxy endcappedpolydioxanone macromers.

As used herein, the terms “polymer”, “polymeric” and similar terms havethe usual meaning known to those skilled in the art and thus may be usedto refer to homopolymers, copolymers (e.g., random copolymer,alternating copolymer, block copolymer, graft copolymer) and mixturesthereof. The repeating structural units of polymers may also be referredto herein as recurring units.

As used herein, the term “molecular weight” has the usual meaning knownto those skilled in the art and thus reference herein to a polymerhaving a particular molecular weight will be understood as a referenceto a polymer molecular weight in units of Daltons. Various techniquesknown to those skilled in the art, such as end group analysis (e.g., by¹H NMR) and high pressure size exclusion chromatography (HPSEC, alsoknown as gel permeation chromatography, “GPC”), may be used to determinepolymer molecular weights. In some cases the molecular weights ofpolymers are further described herein using the terms “number average”molecular weight (Mn) and/or “weight average” molecular weight (Mw),both of which terms are likewise expressed in units of Daltons and havethe usual meaning known to those skilled in the art.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substitutent is a groupthat may be substituted with one or more group(s) individually andindependently selected from alkyl, alkenyl, alkylyl, cyclo-alkyl, aryl,heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, silyl, trihalomethane-sulfonyl, andamino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. The protecting groups that may form theprotective derivatives of the above subsituents are known to those ofskill in the art and may be found in references such as Greene and Wuts,above.

The terms “radiopaque”, “radio-opaque”, “radiopacity”, “radio-opacity”,“radiopacifying” and similar terms have the usual meaning known to thoseskilled in the art and thus may be used to refer to polymer compositionsthat have been rendered easier to detect using medical imagingtechniques (e.g., by X-ray and/or during fluoroscopy) being theincorporation of heavy atoms into the polymer composition. Suchincorporation may be by mixing, e.g., by mixing an effective amount of aradiopacifying additive such as barium salt or complex, and/or byattachment of effective amounts of heavy atoms to one or more of thepolymers in the polymer composition.

In certain configurations, polymer compositions may be inherentlyradiopaque. The term “inherently radiopaque” is used herein to refer toa polymer to which a sufficient number of heavy atoms are attached bycovalent or ionic bonds to render the polymer radiopaque. This meaningis consistent with the understanding of those skilled in the art, see,e.g., U.S. Patent Publication No. 2006/0024266, which is herebyincorporated by reference for all purposes, including for the particularpurpose of describing radiopaque polymeric materials.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent may beselected from one or more of the indicated substituents.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” or “substituted” it is meant that thesubstituent is a group that may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl,hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto,cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, and amino, including mono- and di-substitutedamino groups, and the protected derivatives thereof. Similarly, the term“optionally ring-halogenated” may be used to refer to a group thatoptionally contains one or more (e.g., one, two, three or four) halogensubstituents on the aryl and/or heteroaryl ring. The protecting groupsthat may form the protective derivatives of the above substituents areknown to those of skill in the art and may be found in references suchas Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed.,John Wiley & Sons, New York, N.Y., 1999, which is hereby incorporated byreference in its entirety.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure or be stereoisomeric mixtures. Inaddition it is understood that, in any compound having one or moredouble bond(s) generating geometrical isomers that can be defined as Eor Z each double bond may independently be E or Z a mixture thereof.Likewise, all tautomeric forms are also intended to be included.

The following abbreviations are used to identify various iodinatedcompounds. TE stands for tyrosine ethyl ester, DAT stands fordesaminotyrosine and DTE for desaminotyrosyl tyrosine ethyl ester. PTEstands for hydroxy-phenoxy-1-oxoethyl tyrosine ethyl ester. Ty standsfor tyrosol. The polymer obtained by phosgenation of DTE is denoted aspoly(DTE carbonate). An “I” before the abbreviation showsmono-iodination (e.g. ITE stands for mono-iodinated TE) and an I₂ beforethe abbreviation shows di-iodination (e.g. I₂DAT stands for di-iodinatedDAT). In DTE, if the “I” is before D, it means the iodine is on DAT andif “I” is after D, it means the iodine is on the tyrosine ring (e.g.DI₂TE stands for DTE with 2 iodine atoms on the tyrosine ring). Thefollowing diagram illustrates this nomenclature further.

General Structure of Iodinated DTE Monomer

-   -   IDTE: X^(1a)═I, X^(1b)═H, X^(2a)═H, X^(2b)═H    -   I₂DTE: X^(1a)═I, X^(1b)═I, X^(2a)═H, X^(2b)═H    -   DI₂TE: X^(1a)═H, X^(1b)═H, X^(2a)═I, X^(2b)═I    -   IDITE: X^(1a)═I, X^(1b)═H, X^(2a)═I, X^(2b)═H

As used herein, in its most general form, the abbreviation “HBA” mayrefer to any or all of the hydroxy-arylcarboxylic acid moieties know ashydroxybenzoic acid, it being understood that there are three aredifferent isomers of monohydroxybenzoic acid: 4-hydroxybenzoic acid(para-hydroxybenzoic acid, sometimes abbreviated PHBA), 3-hydroxybenzoicacid (meta-hydroxybenzoic acid), and 2-hydroxybenzoic acid(ortho-hydroxybenzoic acid or salicylic acid). It will be understood byone of ordinary skill in the art that any one of these may included invarious ones of the general monomer and polymer concepts describedherein with reference to hydroxybenzoic acid, being duly cognizant ofany different chemical and biological properties or characteristics ofeach isomer. However, the most typically preferred examples ofhydroxybenzoic acid herein include the 4-hydroxybenzoic acid isomer. Forthis reason, the terms hydroxybenzoic acid or HBA will herein generallyrefer to 4-hydroxybenzoic acid as a preferred example among the threepossible isomers, unless otherwise specified.

For PTE, PTH, IPTE, I₂PTE, PI₂TE, etc., the DAT —CH₂CH₂— group isreplaced with —OCH₂—.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUPCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “halogen atom,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with bromine and iodinebeing preferred.

The term “ester” refers to a chemical moiety with formula—(R)_(n)—COOR′, where R and R are independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ringcarbon) and heteroalicyclic (bonded through a ring carbon), and where nis 0 or 1. An “ester linkage” is an ester group that links two chemicalmoieties to one another.

The terms “purified,” “substantially purified,” and “isolated” as usedherein refer to compounds disclosed herein being substantially free ofother, dissimilar compounds with which the compounds of the inventionare normally associated in their natural state, so that the compounds ofthe invention comprise at least 0.5%, 1%, 5%, 10%, or 20%, and mostpreferably at least 50% or 75% of the mass, by weight, of a givensample.

It is understood that the polymers described herein may be used inaccordance with preferred aspects of the invention as a homogeneouspolymer, as a copolymer, and/or as a polymer blend. Accordingly, forexample, reference herein to a polymer of the Formula (I) is understoodto be a reference to a polymer that comprises a recurring unit of theFormula (I), which may be a homopolymer, copolymer or blend. Likewise,as another example, reference herein to a polymer of the Formula (Ia) isunderstood to be a reference to a polymer that comprises a recurringunit of the Formula (Ia), which may be a homopolymer, copolymer orblend.

Although the inventors do not wish to be bound by or to any particulartheory of operation, the inventors believe that the beneficialcombination of properties associated with the medical devices of thepresent invention are attributable, at least in part, to certaincharacteristics of the polymers of Formula (Ia), from which the devicesare made.

The bioresorbable, inherently radiopaque stents disclosed in accordancewith preferred embodiments of the present invention may be used, forexample, to temporarily treat a blood vessel as in traditionalapplications which generally include delivery through a catheter.

In some embodiments polymers prepared from sufficient amounts of the themonomeric starting materials described herein and having at least onebromine- or iodine-substituted aromatic ring are radio-opaque, such asthe polymers prepared from radiopaque diphenol compounds preparedaccording to the disclosure of U.S. Pat. No. 6,475,477, as well as hedisclosure of co-pending and commonly-owned U.S. patent application Ser.No. 10/592,202, the disclosures of both of which are incorporated hereinby reference. The iodinated and brominated diphenol monomers of thepresent invention can also be employed as radio-opacifying,biocompatible non-toxic additives for other polymeric biomaterials.

Bromine and iodine substituted aromatic monomers of the presentinvention can be prepared by well-known iodination and brominationtechniques that can be readily employed by those of ordinary skill inthe art in view of the guidance provided herein without undueexperimentation. In some embodiments, the halogenated aromatic compoundsfrom which the halogenated aromatic monomers of the present inventionare prepared typically undergo ortho-directed halogenation. The term“ortho-directed” is used herein to designate orientation of the halogenatom(s) relative to the phenoxy alcohol group.

The polymers described herein include polymers prepared by polymerizingFormula (III) monomers having pendent free carboxylic acid groups.However, it is not possible to polymerize polymers having pendent freecarboxylic acid groups from corresponding monomers with pendent freecarboxylic acid groups without cross-reaction of the free carboxylicacid group with the co-monomer. Accordingly, polymers in accordance withthe present invention having pendent free carboxylic acid groups areprepared from homopolymers and copolymers of benzyl and tert-butyl estermonomers of the present invention.

The benzyl ester homopolymers and copolymers may be converted tocorresponding free carboxylic acid homopolymers and copolymers throughthe selective removal of the benzyl groups by the palladium catalyzedhydrogenolysis method disclosed by co-pending and commonly owned U.S.Pat. No. 6,120,491, the disclosure of which is incorporated herein byreference.

The tert-butyl ester homopolymers and copolymers may be converted tocorresponding free carboxylic acid homopolymers and copolymers throughthe selective removal of the tert-butyl groups by the acidolyis methoddisclosed by the above-referenced U.S. patent application Ser. No.10/592,202, also incorporated herein by reference.

After polymerization, appropriate work up of the polymers in accordancewith preferred embodiments of the present invention may be achieved byany of a variety of known methods commonly employed in the field ofsynthetic polymers to produce a variety of useful articles with valuablephysical and chemical properties, all derived from tissue compatiblemonomers. The useful articles can be shaped by conventionalpolymer-forming techniques such as extrusion, compression molding,injection molding, solvent casting, spin casting, wet spinning,combinations of two or more thereof, and the like. Shaped articlesprepared from the polymers are useful, inter alia, as degradablebiomaterials for medical implant applications. Such applications includethe use of shaped articles as vascular grafts and stents.

Polymers according to the present invention also include polyethers,polyurethanes, poly(carbamates), poly(thiocarbonates),poly(carbonodithionates) and poly(thiocarbamates), which may be preparedfrom the diphenol compounds of the present invention in accordance withknown methods.

Random or block copolymers of the polymers of the present invention witha poly(alkylene oxide) may be prepared according to the method disclosedin U.S. Pat. No. 5,658,995, the disclosure of which is also incorporatedby reference. The poly(alkylene oxide) is preferably a poly(ethyleneglycol) block/unit typically having a molecular weight of less thanabout 10,000 per unit. More typically, the poly(ethylene glycol)block/unit has a molecular weight less than about 4000 per unit. Themolecular weight is preferably between about 1000 and about 2000 perunit.

Alternatively, the block copolymers of the polymers of the presentinvention comprise a poly(alkylene oxide) macromer having the formula:

where B is —O—((CH₂)_(p)—O)_(q)— or —O—(CH₂CH(CH₃)—O)_(q)—;

p is an integer ranging from 1 to about 6, preferably 1 to 3; morepreferably 2;

q is about 5 to about 3000, preferably about 10 to about 300, morepreferably about 20 to about 200, still more preferably about 50 toabout 100;

and A¹ is selected from the group consisting of:

where R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀ alkyl,C₁-C₃₀heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀ heteroalkenyl,and C₂-C₃₀ heteroalkynyl.

The molar fraction of poly(ethylene glycol) units in block copolymersmay range from greater than zero to less than 1, and is typicallygreater than zero up to about 0.5, inclusive. More preferably, the molarfraction is less than about 0.25 and yet more preferably, less thanabout 0.1. In a more preferred variations, the molar fraction may varyfrom greater than about 0.001 to about 0.08, and most preferably,between about 0.025 and about 0.035.

Unless otherwise indicated, the molar fractions reported herein arebased on the total molar amount of poly(alkylene glycol) and non-glycolunits in the polymers.

After polymerization, appropriate work up of the polymers in accordancewith preferred embodiments of the present invention may be achieved byany of a variety of known methods commonly employed in the field ofsynthetic polymers to produce a variety of useful articles with valuablephysical and chemical properties, all derived from tissue compatiblemonomers. The useful articles can be shaped by conventional polymerthermo-forming techniques such as extrusion and injection molding whenthe degradation temperature of the polymer is above the glass transitionor crystalline melt temperature, or conventional non-thermal techniquescan be used, such as compression molding, injection molding, solventcasting, spin casting, wet spinning. Combinations of two or more methodscan be used. Shaped articles prepared from the polymers are useful,inter alia, as degradable biomaterials for medical implant applications.

Those skilled in the art will recognize that by appropriate selection ofvariable groups, embodiments of the compounds described above can be ahydroxyphenyl-alkanoic acid, such as desaminotyrosyl tyrosine (DAT), ora hydroxyphenylalkenoic acid. When the compound of the formulaHX³-D¹-X⁴H is a diol, the two compounds may be reacted in an acidcatalyzed Fischer esterification reaction, illustrated generally asfollows:

Because this reaction is reversible, removing water from the reactionmixture shifts the equilibrium to the right. Water removal is usuallyaccomplished by way of azeotropic distillation; however other techniquesknown in the art may be employed as well. In instances where azeotropicdistillation is desired, the solvent used for the reaction is preferablycarefully chosen so that it forms an azeotropic mixture with water.Generally, solvents such as toluene, heptane, chloroform,tetrachloethylene are preferred.

The main advantage of this reaction is that primary and secondaryalcohols form esters with carboxylic acids under acid catalysis, whereasthe phenolic hydroxy groups are unreactive under these conditions. Thusthe carboxylic acid groups of certain compounds, such as the3-(4-hydroxyphenyl) propionic acid (DAT) and of3-(3,5-diiodo-4-hydroxy-phenyl) propionic acid (I₂DAT), can be reactedwith primary or secondary alcohols while the phenolic groups remainintact. An example of the foregoing is is generally illustrated inScheme 4 above, and also as follows in synthetic Scheme 15:

In Scheme 15, X can be R^(4a) as defined above. Polymer compositions asdescribed herein also include polyethers, polyesters,poly-iminocarbonates, polyphosphoesters and polyphosphazines. Thoseskilled in the art can prepare these polymers using routineexperimentation informed by the guidance provided herein. Polyesters,specifically poly(ester amides), may be prepared by the processdisclosed by U.S. Pat. No. 5,216,115, the disclosure of which isincorporated by reference, and particular-ly for the purpose ofdescribing such processes. Polyiminocarbonates may be prepared by theprocess disclosed by U.S. Pat. No. 4,980,449, the disclosure of which isincorporated by reference, and particularly for the purpose ofdescribing such processes. Polyethers may be prepared by the processdisclosed by U.S. Pat. No. 6,602,497, the disclosure of which isincorporated by reference, and particularly for the purpose ofdescribing such processes.

Medical Uses

Various embodiments of the polymer compositions described herein,preferably derived from tissue compatible monomers, may be used toproduce a variety of useful articles with valuable physical and chemicalproperties. The useful articles can be shaped by conventional polymerthermo-forming techniques such as extrusion and injection molding whenthe degradation temperature of the polymer is above the glass transitionor crystalline melt temperature(s), or conventional non-thermaltechniques can be used, such as compression molding, injection molding,solvent casting, spin casting, wet spinning Combinations of two or moremethods can be used. Shaped articles prepared from the polymers areuseful, inter alia, as biocompatible, biodegradable and/or bioresorbablebiomaterials for medical implant applications.

In one embodiment, the medical device is a stent. It is contemplatedthat a stent may comprise many different types of forms. For instance,the stent may be an expandable stent. In another embodiment, the stentmay be configured to have the form of a sheet stent, a braided stent, aself-expanding stent, a woven stent, a deformable stent, or aslide-and-lock stent. Stent fabrication processes may further includetwo-dimensional methods of fabrication such as cutting extruded sheetsof polymer, via laser cutting, etching, mechanical cutting, or othermethods, and assembling the resulting cut portions into stents, orsimilar methods of three-dimensional fabrication of devices from solidforms.

In certain other embodiments, the polymers are formed into coatings onthe surface of an implantable device, particularly a stent, made eitherof a polymer as described herein or another material, such as metal.Such coatings may be formed on stents via techniques such as dipping,spray coating, combinations thereof, and the like. Further, stents maybe comprised of at least one fiber material, curable material, laminatedmaterial and/or woven material. The medical device may also be a stentgraft or a device used in embolotherapy.

The highly beneficial combination of properties associated withpreferred embodiments of the polymers described herein means thesepolymers are well-suited for use in producing a variety of resorbablemedical devices besides stents, especially implantable medical devicesthat are preferably radiopaque, biocompatible, and have various times ofbioresorption. For example the polymers are suitable for use inresorbable implantable devices with and without therapeutic agents,device components and/or coatings with and without therapeutic agentsfor use in other medical systems, for instance, the musculoskeletal ororthopedic system (e.g., tendons, ligaments, bone, cartilage skeletal,smooth muscles); the nervous system (e.g., spinal cord, brain, eyes,inner ear); the respiratory system (e.g., nasal cavity and sinuses,trachea, larynx, lungs); the reproductive system (e.g., male or femalereproductive); the urinary system (e.g., kidneys, bladder, urethra,ureter); the digestive system (e.g., oral cavity, teeth, salivaryglands, pharynx, esophagus, stomach, small intestine, colon), exocrinefunctions (biliary tract, gall bladder, liver, appendix, recto-analcanal); the endocrine system (e.g., pancreas/islets, pituitary,parathyroid, thyroid, adrenal and pineal body), the hematopoietic system(e.g., blood and bone marrow, lymph nodes, spleen, thymus, lymphaticvessels); and, the integumentary system (e.g., skin , hair, nails, sweatglands, sebaceous glands).

The polymers described herein can thus be used to fabricate woundclosure devices, hernia repair meshes, gastric lap bands, drug deliveryimplants, envelopes for the implantation of cardiac devices, devices forother cardiovascular applications, non-cardiovascular stents such asbiliary stents, esophageal stents, vaginal stents, lung-trachea/bronchusstents, and the like.

In addition, the resorbable polymers are suitable for use in producingimplantable, radiopaque discs, plugs, and other devices used to trackregions of tissue removal, for example, in the removal of canceroustissue and organ removal, as well as, staples and clips suitable for usein wound closure, attaching tissue to bone and/or cartilage, stoppingbleeding (homeostasis), tubal ligation, surgical adhesion prevention,and the like. Applicants have also recognized that preferred embodimentsof the polymers described herein are well-suited for use in producing avariety of coatings for medical devices, especially implantable medicaldevices.

Further, in some preferred embodiments, the present polymers may beadvantageously used in making various resorbable orthopedic devicesincluding, for example, radiopaque biodegradable screws (interferencescrews), radiopaque biodegradable suture anchors, and the like for usein applications including the correction, prevention, reconstruction,and repair of the anterior cruciate ligament (ACL), the rotatorcuff/rotator cup, and other skeletal deformities.

Other devices that can be advantageously formed from preferredembodiments of the polymers described herein, include devices for use intissue engineering. Examples of suitable resorbable devices includetissue engineering scaffolds and grafts (such as vascular grafts, graftsor implants used in nerve regeneration). The resorbable polymers mayalso be used to form a variety of devices effective for use in closinginternal wounds. For example biodegradable resorbable sutures, clips,staples, barbed or mesh sutures, implantable organ supports, and thelike, for use in various surgery, cosmetic applications, and cardiacwound closures can be formed.

Various devices useful in dental applications may advantageously beformed according to embodiments of the described herein. For exampledevices for guided tissue regeneration, alveolar ridge replacement fordenture wearers, and devices for the regeneration of maxilla-facialbones may benefit from being radiopaque so that the surgeon or dentistcan ascertain the placement and continuous function of such implants bysimple X-ray imaging.

Preferred embodiments of the polymers described herein are also usefulin the production of bioresorbable, inherently radiopaque polymericembolotherapy products for the temporary and therapeutic restriction orblocking of blood supply to treat tumors and vascular malformations,e.g., uterine fibroids, tumors (i.e., chemoembolization), hemorrhage(e.g., during trauma with bleeding) and arteriovenous malformations,fistulas and aneurysms delivered by means of catheter or syringe.Details of embolotherapy products and methods of fabrication in whichthe polymers described herein may be employed are disclosed in U.S.Patent Publication No. 20050106119 A1, the disclosure of which isincorporated by reference, and particularly for the purpose ofdescribing such products and methods. Embolotherapy treatment methodsare by their very nature local rather than systemic and the products arepreferably fabricated from the radio-opaque polymers described herein,to permit fluoroscopic monitoring of delivery and treatment.

The polymers described herein are further useful in the production of awide variety of therapeutic agent delivery devices. Such devices may beadapted for use with a variety of therapeutics including, for example,pharmaceuticals (i.e., drugs) and/or biological agents as previouslydefined and including biomolecules, genetic material, and processedbiologic materials, and the like. Any number of transport systemscapable of delivering therapeutics to the body can be made, includingdevices for therapeutics delivery in the treatment of cancer,intravascular problems, dental problems, obesity, infection, and thelike.

A medical device that comprises a polymeric material may include one ormore additional components, e.g., a plasticizer, a filler, acrystallization nucleating agent, a preservative, a stabilizer, aphotoactivation agent, etc., depending on the intended application. Forexample, in an embodiment, a medical device comprises an effectiveamount of at least one therapeutic agent and/or a magnetic resonanceenhancing agent. Non-limiting examples of preferred therapeutic agentsinclude a chemotherapeutic agent, a non-steroidal anti-inflammatory, asteroidal anti-inflammatory, and a wound healing agent. Therapeuticagents may be co-administered with the polymeric material. In apreferred embodiment, at least a portion of the therapeutic agent iscontained within the polymeric material. In another embodiment, at leasta portion of the therapeutic agent is contained within a coating on thesurface of the medical device.

Non-limiting examples of preferred chemotherapeutic agents includetaxanes, taxinines, taxols, paclitaxel, dioxorubicin, cis-platin,adriamycin and bleomycin. Non-limiting examples of preferrednon-steroidal anti-inflammatory compounds include aspirin,dexamethasone, ibuprofen, naproxen, and Cox-2 inhibitors (e.g.,Rofexcoxib, Celecoxib and Valdecoxib). Non-limiting examples ofpreferred steroidal anti-inflammatory compounds include dexamethasone,beclomethasone, hydrocortisone, and prednisone. Mixtures comprising oneor more therapeutic agents may be used. Non-limiting examples ofpreferred magnetic resonance enhancing agents include gadolinium saltssuch as gadolinium carbonate, gadolinium oxide, gadolinium chloride, andmixtures thereof.

The amounts of additional components present in the medical device arepreferably selected to be effective for the intended application. Forexample, a therapeutic agent is preferably present in the medical devicein an amount that is effective to achieve the desired therapeutic effectin the patient to whom the medical device is administered or implanted.Such amounts may be determined by routine experimentation. In certainembodiments, the desired therapeutic effect is a biological response. Inan embodiment, the therapeutic agent in the medical device is selectedto promote at least one biological response, preferably a biologicalresponse selected from the group consisting of thrombosis, cellattachment, cell proliferation, attraction of inflammatory cells,deposition of matrix proteins, inhibition of thrombosis, inhibition ofcell attachment, inhibition of cell proliferation, inhibition ofinflammatory cells, and inhibition of deposition of matrix proteins. Theamount of magnetic resonance enhancing agent in a medical devices ispreferably an amount that is effective to facilitate radiologic imaging,and may be determined by routine experimentation.

The term “pharmaceutical agent”, as used herein, encompasses a substanceintended for mitigation, treatment, or prevention of disease thatstimulates a specific physiologic (metabolic) response. The term“biological agent”, as used herein, encompasses any substance thatpossesses structural and/or functional activity in a biological system,including without limitation, organ, tissue or cell based derivatives,cells, viruses, vectors, nucleic acids (animal, plant, microbial, andviral) that are natural and recombinant and synthetic in origin and ofany sequence and size, antibodies, polynucleotides, oligonucleotides,cDNA's, oncogenes, proteins, peptides, amino acids, lipoproteins,glycoproteins, lipids, carbohydrates, polysaccharides, lipids,liposomes, or other cellular components or organelles for instancereceptors and ligands. Further the term “biological agent”, as usedherein, includes virus, serum, toxin, antitoxin, vaccine, blood, bloodcomponent or derivative, allergenic product, or analogous product, orarsphenamine or its derivatives (or any trivalent organic arseniccompound) applicable to the prevention, treatment, or cure of diseasesor injuries of man (per Section 351(a) of the Public Health Service Act(42 U.S.C. 262(a)). Further the term “biological agent” may include 1)“biomolecule”, as used herein, encompassing a biologically activepeptide, protein, carbohydrate, vitamin, lipid, or nucleic acid producedby and purified from naturally occurring or recombinant organisms,antibodies, tissues or cell lines or synthetic analogs of suchmolecules; 2) “genetic material” as used herein, encompassing nucleicacid (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA),genetic element, gene, factor, allele, operon, structural gene,regulator gene, operator gene, gene complement, genome, genetic code,codon, anticodon, messenger RNA (mRNA), transfer RNA (tRNA), ribosomalextrachromosomal genetic element, plasmagene, plasmid, transposon, genemutation, gene sequence, exon, intron, and, 3) “processed biologics”, asused herein, such as cells, tissues or organs that have undergonemanipulation. The therapeutic agent may also include vitamin or mineralsubstances or other natural elements.

For devices placed in the vascular system, e.g., a stent, the amount ofthe therapeutic agent is preferably sufficient to inhibit restenosis orthrombosis or to affect some other state of the stented tissue, forinstance, heal a vulnerable plaque, and/or prevent rupture or stimulateendothelialization. The agent(s) may be selected from the groupconsisting of antiproliferative agents, anti-inflammatory, anti-matrixmetalloproteinase, and lipid lowering, cholesterol modifying,anti-thrombotic and antiplatelet agents, in accordance with preferredembodiments of the present invention. In some preferred embodiments ofthe stent, the therapeutic agent is contained within the stent as theagent is blended with the polymer or admixed by other means known tothose skilled in the art. In other preferred embodiments of the stent,the therapeutic agent is delivered from a polymer coating on the stentsurface. In another preferred variation the therapeutic agent isdelivered by means of no polymer coating. In other preferred embodimentsof the stent, the therapeutic agent is delivered from at least oneregion or one surface of the stent. The therapeutic may be chemicallybonded to the polymer or carrier used for delivery of the therapeutic ofat least one portion of the stent and/or the therapeutic may bechemically bonded to the polymer that comprises at least one portion ofthe stent body. In one preferred embodiment, more than one therapeuticagent may be delivered.

In certain embodiments, any of the aforementioned devices describedherein can be adapted for use as a therapeutic delivery device (inaddition to any other functionality thereof). Controlled therapeuticdelivery systems may be prepared, in which a therapeutic agent, such asa biologically or pharmaceutically active and/or passive agent, isphysically embedded or dispersed within a polymeric matrix or physicallyadmixed with a polymer described herein. Controlled therapeutic agentdelivery systems may also be prepared by direct application of thetherapeutic agent to the surface of an implantable medical device suchas a bioresorbable stent device (comprised of at least one of thepolymers described herein) without the use of these polymers as acoating, or by use of other polymers or substances for the coating.

Therapeutic agent delivery compounds may also be formed by physicallyblending the therapeutic agent to be delivered with the polymersdescribed herein using conventional techniques well-known to those ofordinary skill in the art. For this therapeutic agent deliveryembodiment, it is not essential that the polymer have pendent groups forcovalent attachment of the therapeutic agent.

The polymer compositions described herein containing therapeutic agents,regardless of whether they are in the form of polymer conjugates orphysical admixtures of polymer and therapeutic agent, are suitable forapplications where localized delivery is desired, as well as insituations where a systemic delivery is desired. The polymer conjugatesand physical admixtures may be implanted in the body of a patient inneed thereof, by procedures that are essentially conventional andwell-known to those of ordinary skill in the art.

The polyarylates can also be formed into drug delivery implants thatdegrade to release pharmacologically or biologically active agentswithin a predictable controlled release time. Such controlled drugdelivery systems can be prepared by incorporating the active agents intothe polymer chains as pendant side chains or by cross linking thependant side chains to form a polymeric matrix into which the activeagents are physically embedded or dispersed. Controlled drug deliverysystem implants can also be formed by physically admixing thepolyarylates with a biologically or pharmacologically active agent. Theforegoing procedures are essentially conventional and well-known tothose of ordinary skill in the art.

For controlled drug delivery systems in which a biologically orpharmacologically active agent is physically embedded or dispersed intoa polymeric matrix or physically admixed with a polyarylate, suitablebiologically or pharmacologically active agents include in principle anyactive agent that has to be repeatedly administered over prolongedperiods of time.

An advantage of using the radiopaque, bioresorbable polymers describedherein in therapeutic agent delivery applications is the ease ofmonitoring release of a therapeutic agent and the presence of theimplantable therapeutic delivery system. Because the radiopacity of thepolymeric matrix is due to covalently attached halogen substituents, thelevel of radiopacity is directly related to the residual amount of thedegrading therapeutic agent delivery matrix still present at the implantsite at any given time after implantation. In preferred embodiments therate of therapeutic release from the degrading therapeutic deliverysystem will be correlated with the rate of polymer resorption. In suchpreferred embodiments, the straight-forward, quantitative measurement ofthe residual degree of radio-opacity will provide the attendingphysician with a way to monitor the level of therapeutic release fromthe implanted therapeutic delivery system.

The following non-limiting examples set forth herein below illustratecertain aspects of the invention. All parts and percentages are by molepercent unless otherwise noted and all temperatures are in degreesCelsius unless otherwise indicated. All solvents were HPLC grade and allother reagents were of analytical grade and used as received, unlessotherwise indicated.

EXAMPLES

All reagents were purchased from commercial sources in pure form andwere used as received. Solvents were of “HPLC” or “ACS reagent” grade.

Generally, the diphenolic monomers were prepared byFisher-esterification of tyrosol with phenolic acids such asdesaminotyrosine, 3,5-diiododesaminotyrosine or dicarboxylic acids (0.5equivalents) by refluxing with catalytic amount of 4-toulenesulfonicacid in chloroform or 1,2-dichloroethane as the solvent. A modified DeanStark trap was used to remove the water formed. The diphenolic monomersin the pure form or as appropriate mixtures were polymerized to thecorresponding polycarbonates using triphosgene. The polymers werecompression molded into films. The films were tested for mechanicalproperties and they generally showed high modulus, tensile strength, andelongation at break. Further details are provided below.

Example 1A Synthesis of 4-hydroxyphenethyl 3-(4-hydroxyphenyl)propanoate(DTy) and Related Diphenol Monomers

Into a 500 mL round bottomed flask fitted with an overhead stirrer, anda modified Dean-stark trap for solvents heavier than water were added 10g (72 mmol) of tyrosol, 13 g (78 mmol) of desaminotyrosine (DAT), 0.65 g(3.4 mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of1,2-dichloroethane (DCE). A water-cooled reflux condenser was placed ontop of the modified Dean-stark trap and the contents of the flask wereheated to reflux while being stirred. The reaction was continued untilapproximately 1.4 mL of water collected in the modified Dean-stark trapabove the DCE and the water collection essentially stopped (about 4hours of reflux). The reaction mixture was cooled to room temperaturewhen the crude product precipitated as off-white crystalline solid,which was dissolved in 100 mL of ethyl acetate and washed twice with 100mL portions of 5% sodium bicarbonate solution. After drying overmagnesium sulfate the organic layer was concentrated and precipitatedwith hexane. The resulting white crystalline solid was collected byfiltration and dried in a vacuum oven at 25° C. The product wascharacterized by elemental analysis, HPLC, and ¹H NMR.

Using a similar procedure, 4′-hydroxyphenethyl-4-hydroxyphenyl acetate(HPTy, compound of Formula (V) where L¹=L⁴=bond, m=2, n=1, y1=y2=0) wasprepared by substituting 4-hydroxyphenyl acetic acid fordesaminotyrosine. The product was characterized by hplc and ¹H NMR.

Using a similar procedure, 4-hydroxyphenethyl 2-(4-hydroxyphenoxy)acetate (compound of Formula (V) where L¹=bond, L⁴=—O—, m=2, n=1,y1=y2=0) is prepared by substituting 2-(4-hydroxyphenoxy)acetic acid fordesaminotyrosine. Similar results are obtained.

Using similar procedures, a monomer having the structure below (compoundof Formula (VI) where Z═—NH—C(O)—CH₃, X¹═I, y1=2, y2=0) is prepared byreacting N-acetyltyrosine with diiodotyrosol using a solvent or mixtureof solvents in which the N-acetyl tyrosine is more soluble than in1,2-dichloroethane Similar results are obtained.

Using similar procedures, a monomer having the structure below (compoundof Formula (VI) where Z═—NH—C(O)—CH₃, y1=y2=0) is prepared by reactingN-acetyltyrosine with tyrosol using a solvent or mixture of solvents inwhich N-acetyl tyrosine is more soluble than in 1,2-dichloroethaneSimilar results are obtained.

Example 1B Synthesis of tyrosol ester of 4-hydroxybenzoic acid(tyrosyl(4-hydroxy-benzoate), BTy)

Into a 250 mL round bottomed flask fitted with a Dean-Stark trap and anoverhead stirrer is added 69.0 g (0.5 mol) of hydroxybenzoic acid, 66.3g (0.49 mol) of tyrosol and 0.2 g of Sb₂O₃. The flask is heated in a noil bath maintained at 210° C. while stirring with the overhead stirrer.The solid mixture melts into a clear liquid and water of reactiondistilled over and collected in the Dean-Stark trap. When the waterstops coming over the reaction was stopped. The reaction mixture wasallowed to cool to room temperature. The ¹H NMR spectrum of the solid isin agreement with structure. The product is purified byrecrystallization.

Example 2A Synthesis of 4-hydroxyphenethyl3-(4-hydroxy-3,5-diiodophenyl)-propanoate (I₂DTy) and Related Compounds

Into a 500 mL round bottomed flask fitted with an overhead stirrer, anda modified Dean-stark trap for solvents heavier than water were added34.5 g (0.250 mol) of tyrosol, 102 g (0.244 mol) of3-(4-hydroxy-3,5-diiodophenyl)propanoic acid (I₂DAT), 4.76 g (0.025 mol)of 4-toluenesulfonic acid monohydrate, and 500 mL of DCE. A water-cooledreflux condenser was placed on top of the modified Dean-stark trap andthe contents of the flask were heated to reflux while being stirred. Thereaction was continued until approximately 4.8 mL of water collected inthe modified Dean-stark trap above the DCE and the water collectionessentially stopped. The reaction mixture was allowed to cool to roomtemperature when the crude product precipitated as off-white crystalswhich was dried and then dissolved in 350 mL of tetrahydrofuran (thf).To this solution was added while stirring 1 L of 5% aqueous sodiumbicarbonate solution stirred for 10 m and then allowed stand when thelayers separated. The top layer was removed and discarded. The bottomlayer was washed with two 500 mL portions of 5% aqueous sodiumbicarbonate solution. I₂DTy precipitated as white crystalline solid.This was isolated by filtration and washed with 3×50 mL of deionizedwater. The product was dried under vacuum at 40° C. for 24 h andcharacterized by elemental analysis, HPLC, and ¹H NMR.

Using similar procedures,4′-hydroxyphenethyl-2-(4-hydroxy-3,5-diiodophenyl)acetate (I₂HPTy) wasprepared by substituting 2-(4-hydroxy-3-5-diiodophenyl)acetic acid forI₂DAT, and characterized by hplc and ¹H NMR.

Using similar procedures,4′-hydroxy-3′,5′-diiodophenethyl-2-(4-hydroxy-3,5-diiodophenyl)propionateis prepared by substituting 4-(2-hydroxyethyl)-2,6-diiodophenol fortyrosol.

Example 2B Synthesis of 3′,5′-diiodotyrosyl3,5-diiodo(4-hydroxybenzoate), (I4BTy)

As described above, preparation of halogenated diphenolic monomersincluding hydroxybenzoic acid by reaction of halogenated precursors isproblematic, due to halogen loss during reaction. Thus, by using anon-halogenated diphenolic HBA-tyrosol ester precursor in a halogenationreaction, a multiply-halogenated monomer is prepared. Thetyrosyl(4-hydroxybenzoate), (BTy) prepared in Example 1B may be used.

Method 1: Tyrosyl(4-hydroxybenzoate) (64.6 g, 0.25 mol) was heated with250 mL of 95% ethanol to reflux in 1 L round bottomed flask with anoverhead stirrer under a N₂ atmosphere. The solid partially dissolvedand to the suspension was added 139.7 g (0.55 mol) of iodine. Through anaddition funnel 39 g (0.07 mol) of potassium iodate dissolved in 440 mLof deionized water was added to the reaction mixture over 15 min Thereaction mixture was heated to reflux for 2 h while stirring vigorously.The reaction mixture was then cooled to room temperature. The pinkcolored precipitate was isolated by filtration and washed with a 10%Na₂S₂O₃ solution followed by washing with water. The product was driedin a vacuum oven at 40° C. The product was purified byrecrystallization. Product was characterized by ¹H NMR, HPLC, andelemental analysis.

Method 2: In a 500 mL flask a mixture of 17.1 g oftyrosyl(4-hydroxybenzoate), 34 g of iodine, 100 mL of 95% ethanol, and 9mL of sulfuric acid was stirred with a magnetic stirrer and heated to60° C. using a water bath. To this was then added 21 mL of 30% aqueousH₂O₂ using an addition funnel over 30 min. After stirring for 30 min,the mixture was cooled and added to 400 mL of water with stirring. Theprecipitate was isolated by filtration and washed with 2 100 mL portionsof acetic acid and then with 2 100 mL portions of acetone. The productwas dried in a vacuum oven at 40° C. It was characterized by ¹H NMR,HPLC, and elemental analysis.

Example 3 Synthesis of Dityrosyl Succinate

Into a 500 mL round bottomed flask fitted with an overhead stirrer, anda modified Dean-stark trap for solvents heavier than water were added25.0 g (0.181 mol) of tyrosol, 9.56 g (0.088 mol) of succinic acid, 3.44g (18.1 mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of DCE.A water-cooled reflux condenser was attached to the top of the modifiedDean-stark trap and the contents of the flask were heated to refluxwhile being stirred. The reaction was continued until approximately 3.2mL of water collected in the modified Dean-stark trap above the DCE andthe water collection essentially stopped. The reaction mixture wasallowed to cool to room temperature while stirring was continued. Theproduct that precipitated was isolated by filtration and washed with2×50 mL of DCE. ¹H NMR showed residual PTSA and tyrosol. Forpurification the solid was stirred with 150 mL of aqueous 5% NaHCO₃ for3 h using overhead stirrer. The product was isolated by filtration andwashed with 3×50 mL of DI water and then dried in the vacuum oven for 24h at 50° C. The product was dried under vacuum at 40° C. for 24 h andcharacterized by elemental analysis, HPLC, and ¹H NMR spectroscopy.

Example 4 Synthesis of Dityrosyl Oxalate

Into a 500 mL round bottomed flask fitted with an overhead stirrer, anda modified Dean-stark trap for solvents heavier than water were added25.0 g (0.181 mol) of tyrosol, 8.00 g (0.088 mol) of Oxalic acid, 3.44 g(18.1 mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of 1,2-DCE(dichloroethane). A water-cooled reflux condenser was attached to thetop of the modified Dean-stark trap and the contents of the flask wereheated to reflux while being stirred. The reaction was continued untilapproximately 3.2 mL of water collected in the modified Dean-stark trapabove the DCE and the water collection essentially stopped. The reactionmixture was allowed to cool to room temperature while stirring wascontinued. The product that precipitated was isolated by filtration andwashed with 2×50 mL of DCE. For purification the solid was stirred with150 mL of aqueous 5% NaHCO3 for 3 h using overhead stirrer. The productwas isolated by filtration and washed with 3×50 mL of DI (deionized)water and then dried in the vacuum oven for 24 h at 50° C. The productwas dried under vacuum at 40° C. for 24 h and characterized by elementalanalysis, HPLC, and ¹H NMR spectroscopy.

Example 5 Polymerization of DTy and HPTy Using Triphosgene

In a 500 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 8.0 g (0.035 mol) ofDTy, 9.5 g (0.12 mol) of pyridine, 70 mL of dichloromethane (DCM) andstirred for 15 min to get a clear solution. Triphosgene (3.6 g, 0.036mol) was dissolved in 15 mL of DCM and the solution was introduced intothe reaction flask over 2-3 hours. After the addition was complete, 100mL of water was added to the reaction mixture and stirred for 5 min.After allowing the layers to separate, the top aqueous layer was removedand discarded. The washing as above was repeated with two additional 100mL portions of DI water. The reaction mixture was then precipitated with120 mL of IPA. The resulting gel was ground twice with 150 mL portionsof IPA in 1 L laboratory blender. The product was isolated by vacuumfiltration and dried in a vacuum oven at 80° C. for 24 h. The polymerhad a HPSEC polystyrene equivalent molecular weight of 160 Kda (THF asmobile phase). The polymer was semi-crystalline with a Tg of 51° C. anda Tm of 181° C. On compression molding at 220° C., it gave films whichwere transparent on rapid cooling and translucent when cooled slowly.The tensile modulus, tensile stress at yield, and elongation at breakwere respectively 210 ksi, 5 ksi and 500%.

Using similar procedures, HPTy (4′-hydroxyphenethyl-4-hydroxyphenylacetate, such as obtained in accordance with Example 1) was polymerizedto obtain poly(HPTy carbonate) with an HPSEC polystyrene equivalent Mwof 140 Kda and a Tg of 55° C.

Example 6 Polymerization of I₂DTy and I₂HPTy Using Triphosgene

In a 500 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a controlled liquid addition device were placed 25 g (0.046mol) of I₂DTy, 14.3 g (0.181 mol) of pyridine, 200 mL of DCM and stirredfor 15 min to get a clear solution. Triphosgene (5.1 g, 0.052 mol ofphosgene) was dissolved in 20 mL of DCM and the solution was to thereaction flask over 2-3 hours. After the addition was complete, 250 mLof water was added to the reaction mixture and stirred for 5 min. Afterallowing the layers to separate, the top aqueous layer was removed anddiscarded. The washing was repeated with two additional 250 mL portionsof DI water. The reaction mixture was then precipitated with 350 mL ofIPA. The resulting gel was ground twice with 200 mL portions of IPA in a1 L laboratory blender. The product was isolated by vacuum filtrationand dried in a vacuum oven at 80° C. for 24 h. The polymer had a HPSECpolystyrene equivalent molecular weight of 176 Kda (THF as mobile phase)and glass transition temperature (Tg) of 112° C. Compression molding at205° C. gave a uniform transparent film which gave tensile modulus,tensile stress at yield, and elongation at break respectively of 230ksi, 9.2 ksi and 220%. Using similar procedures, I₂HPTy (obtained inaccordance with Example 2) was polymerized to obtain poly(I₂HPTycarbonate).

Example 7 Preparation of Poly(I₂DTy-co-10 weight % PEG2K Carbonate)

In a 250 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 9.0 g (0.017 mol) ofI₂DTy, 1.01 g of PEG2000, 5.4 g (0.068 mol) of pyridine, and 65 mL ofDCM and stirred for 15 min to get a clear solution. Triphosgene (2.0 g,0.020 mol of phosgene) was dissolved in 10 mL of DCM and the solutionwas introduced into the reaction flask over 2-3 hours. After theaddition was complete, 100 mL of water was added to the reaction mixtureand stirred for 5 min. After allowing the layers to separate, the topaqueous layer was removed and discarded. The washing was repeated withtwo additional 100 mL portions of DI water. The reaction mixture wasthen precipitated with 100 mL of IPA. The resulting gel was ground twicewith 150 mL portions of IPA in 1 L laboratory blender. The product wasisolated by vacuum filtration and dried in a vacuum oven at 50° C. Thepolymer had a HPSEC polystyrene equivalent molecular weight of 250 Kda(THF as mobile phase) and glass transition temperature (Tg) of 64° C.and gave a clear film on compression molding at 205° C. The tensilestress at yield , the tensile modulus and elongation at breakrespectively were 7.1 ksi, 235 ksi and 350%.

Example 8 Preparation of Poly(I₂DTy-co-5 weight % PEG2K Carbonate)

In a 250 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 10 g (0.019 mol) ofI₂DTy, 0.535 g of PEG2000, 5.9 ml (0.073 mol) of pyridine, and 62 mL ofDCM and stirred for 15 min to get a clear solution. Triphosgene (2.1 g,0.021 mol of phosgene) was dissolved in 10 mL of DCM and the solutionwas introduced into the reaction flask over 2-3 hours. After theaddition was complete, 100 mL of water was added to the reaction mixtureand stirred for 5 min. After allowing the layers to separate, the topaqueous layer was removed and discarded. The washing was repeated withtwo additional 100 mL portions of DI water. The reaction mixture wasthen precipitated with 100 mL of IPA. The resulting gel was ground twicewith 150 mL portions of IPA in 1 L laboratory blender. The product wasisolated by vacuum filtration and dried in a vacuum oven at 50° C. Thepolymer had a HPSEC polystyrene equivalent molecular weight of 200 Kda(THF as mobile phase) and glass transition temperature (Tg) of 84° C.Compression molding at 205° C. gave a uniform transparent film whichgave tensile modulus, tensile stress at yield , and elongation at breakrespectively of 232 ksi, 8.2 ksi and 70%.

Example 9 Preparation of Poly(I₂DTy-co-10 weight % PTMC5K Carbonate)

In a 250 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 9.0 g (0.017 mol) ofI₂DTy, 1.00 g of poly(trimethylene carbonate) of Mn 5000 (PTMCSK), 5.5ml (0.068 mol) of pyridine, and 65 mL of DCM and stirred for 15 min toget a clear solution. Triphosgene (1.9 g, 0.019 mol of phosgene) wasdissolved in 10 mL of DCM and the solution was introduced into thereaction flask over 2-3 hours. After the addition was complete, 100 mLof water was added to the reaction mixture and stirred for 5 min. Afterallowing the layers to separate, the top aqueous layer was removed anddiscarded. The washing was repeated with two additional 100 mL portionsof DI water. The reaction mixture was then precipitated with 100 mL ofIPA. The resulting gel was ground twice with 150 mL portions of IPA in 1L laboratory blender. The product was isolated by vacuum filtration anddried in a vacuum oven at 50° C. The polymer had a HPSEC polystyreneequivalent molecular weight of 250 Kda (THF as mobile phase) and glasstransition temperature (Tg) of 101° C. Compression molding at 205° C.gave a uniform transparent film which gave tensile modulus, tensilestress at yield, and elongation at break respectively of 201 ksi, 7.4ksi and 120%.

Example 10 Preparation of Poly(I₂DTy-co-5 weight % PTMC5K Carbonate)

In a 250 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 10 g (0.019 mol) ofI₂DTy, 0.53 g of PTMCSK, 5.9 ml (0.073 mol) of pyridine, and 65 mL ofDCM and stirred for 15 min to get a clear solution. Triphosgene (2.1 g,0.021 mol of phosgene) was dissolved in 10 mL of DCM and the solutionwas introduced into the reaction flask over 2-3 hours. After theaddition was complete, 100 mL of water was added to the reaction mixtureand stirred for 5 min. After allowing the layers to separate, the topaqueous layer was removed and discarded. The washing was repeated withtwo additional 100 mL portions of DI water. The reaction mixture wasthen precipitated with 100 mL of IPA. The resulting gel was ground twicewith 150 mL portions of IPA in 1 L laboratory blender. The product wasisolated by vacuum filtration and dried in a vacuum oven at 50° C. Thepolymer had a HPSEC polystyrene equivalent molecular weight of 225 Kda(THF as mobile phase) and glass transition temperature (Tg) of 106° C.Compression molding at 205° C. gave a uniform transparent film whichgave tensile modulus, tensile stress at yield, and elongation at breakrespectively of 266 ksi, 8.4 ksi and 185%.

Example 11 Synthesis of di-ester of 1,3-propanediol with I₂DAT (PrD-diI2DAT)

Into a 500 mL round-bottomed flask equipped with an overhead stirrer, aDean-Stark trap and a thermometer were added 3.04 g (0.040 mol) of1,3-propanediol, 33.8 g (0.081 mol) of 3,5-diiododesaminotyrosyltyrosine ethyl ester (I₂DAT), 0.76 g (4.0 mmol) of p-toluenesulfonicacid, and 200 mL of 1,2-dichloroethane The flask was heated using aheating mantle, while stirring with the overhead stirrer so that1,2-dichloroethane and water distilled over into the Dean-Stark trap.The heating continued until the water collection stopped (about 1.45 mLof water was collected). The reaction mixture was allowed to cool to 50°C. and then evaporated to dryness. To the residue 175 mL of acetonitrilewas added and stirred at room temperature for 4 h. The crystalline solidthat separated was isolated by filtration and washed with acetonitrile.The Off-white crude product was collected and dried.

The crude PrD-di I2DAT obtained above (98% pure by HPLC) was stirredwith 175 mL of acetonitrile for 4 h using a overhead stirrer at 200 rpm.The product precipitated as almost colorless powder, which showed apurity of ca 98-99% by HPLC. For further purification the product wasdissolved in acetonitrile (10 mL/g) and stirred with Norit (10 mg ofNorit/g of product). The hot solution was filtered to remove Norit andthen cooled in ice-water bath for recrystallization when colorlesspowder was obtained (purity >99.5% by HPLC). The product was dried invacuum oven at 40° C. The product had a melting point of 88° C. (by DSC)and the elemental analysis and ¹H NMR spectrum were in agreement withthe structure. Further purification can be achieved by columnchromatography on silica gel.

Example 12 Preparation of Poly(PrD-di I₂DAT-co-10 weight % TyrosolCarbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 25 g (0.029 mol) ofPrD-di I₂DAT, 2.78 g (0.020 mol) of tyrosol, 15.4 ml (0.19 mol) ofpyridine, and 170 mL of DCM and stirred for 15 min to get a clearsolution. Triphosgene (5.4 g, 0.055 mol of phosgene) was dissolved in 20mL of DCM and the solution was introduced into the reaction flask over2-3 hours. After the addition was complete, the 200 mL of water wasadded to the reaction mixture and stirred for 5 min. After allowing thelayers to separate, the top aqueous layer was removed and discarded. Thewashing was repeated with two additional 200 mL portions of DI water.The reaction mixture was then precipitated with 300 mL of IPA. Theresulting gel was ground twice with 200 mL portions of IPA in 1 Llaboratory blender. The product was isolated by vacuum filtration anddried in a vacuum oven at 80° C. The polymer had a HPSEC polystyreneequivalent molecular weight of 200 Kda (THF as mobile phase) and glasstransition temperature (Tg) of 90° C. ¹H NMR spectrum of the polymer wasin agreement with the structure. Compression molding at 205° C. gave auniform transparent film which gave tensile modulus, tensile stress atyield (σ), and elongation at break respectively of 260 ksi, 9.7 ksi and220%. Using similar procedures copolymers with 5%, and 15% tyrosol wereprepared as follows:

% Modulus, Elongation, tyrosol Tg, ° C. σ, ksi ksi % 5 104 9.8 254 41 1590 9.5 244 164

As will be understood by a person of ordinary skill in the art, sincetriphogene is added slowly into the mixture of the reactants PrD-diI₂DAT and tyrosol, the poly(PrD-di I₂DAT-co-tyrosol carbonate) productis composed of mainly polymer molecules having randomly-ordered PrD-diI₂DAT and tyrosol units connected through carbonate (—OC(O)O—) linkers.That is, two adjacent units could include PrD-di I₂DAT and PrD-di I₂DAT,PrD-di I₂DAT and tyrosol, or tyrosol and tyrosol. Given theunsymmetrical structure of tyrosol, it can be connected with a PrD-diI₂DAT unit using either “head” (i.e., “phenoxy” moiety) or “tail” (i.e.,the “ethylenoxy” moiety). Any two adjacent units formed from tyrosolitself can be in any of the “head-head”, “head-tail” or “tail-tail”arrangements. In this Example, without intending to be bound by theory,since the PrD-di I₂DAT was used in molar excess, the polymer moleculeslikely do not contain a large amount of long strings of“tyrosol-carbonate-tyrsol” units linked to each other. On the otherhand, if there is a large excess of tyrosol relative to the PrD-di I₂DATin the reaction mixture, tyrosol may have more opportunity to link witheach other to give relatively long strings of such linkages.

Example 13 Poly(Tyrosol Carbonate)

In a 500 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 10 g (0.073 mol) oftyrosol, 24 ml (0.298 mol) of pyridine, 200 mL of DCM and stirred for 15min to get a clear solution. Triphosgene (7.7 g, 0.078 mol of phosgene)was dissolved in 25 mL of DCM and the solution was introduced into thereaction flask over 2-3 hours. After the addition was complete, 250 mLof water was added to the reaction mixture and stirred for 5 min. Afterallowing the layers to separate, the top aqueous layer was removed anddiscarded. The washing was repeated with two additional 250 mL portionsof DI water. The reaction mixture was then precipitated with 300 mL ofIPA. The resulting gel was ground twice with 200 mL portions of IPA in 1L laboratory blender. The product was isolated by vacuum filtration anddried in a vacuum oven at 60° C. The polymer had a HPSEC polystyreneequivalent molecular weight of 126 Kda (THF as mobile phase) and glasstransition temperature (Tg) of 58° C. Compression molding at 195° C.gave a uniform transparent film which gave tensile modulus, tensilestress at yield, and elongation at break respectively of 191 ksi, 5 ksiand 450%.

Example 14 Low Molecular Weight Poly(Tyrosol Carbonate)

In a 250 mL 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 10 g (0.073 mol) oftyrosol, 22 ml (0.277 mol) of pyridine, 60 mL of DCM and stirred for 15min to get a clear solution. Triphosgene (7.0 g, 0.071 mol of phosgene)was dissolved in 25 mL of DCM and the solution was introduced into thereaction flask over 2-3 hours. After the addition was complete, the 100mL of 0.2 M aqueous HCl was added to the reaction mixture and stirredfor 5 min. After allowing the layers to separate, the top aqueous layerwas removed and discarded. The washing was repeated with threeadditional 100 mL portions of 0.2 M aqueous HCl. The reaction mixturewas then dried over anhydrous magnesium sulfate and then precipitatedwith 100 mL of hexane. The resulting viscous oil was stirred with 200 mLof fresh hexane until the product solidified into a white solid. Theproduct was transferred to a glass dish dried in a vacuum oven at 60° C.The polymer had a HPSEC polystyrene equivalent Mw of 7500 da and Mn of5700 da (THF as mobile phase) and glass transition temperature (Tg) of48° C. A number of oligomers and polymers ranging in Mw from 750 da to40,000 da were prepared using this method.

Example 15 Preparation of multi-block Poly(PrD-di I₂DAT -co-10 weight %Tyrosol Carbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 25 g (0.029 mol) ofPrD-di I₂DAT, 2.78 g (0.49 mmol) of oligo(tyrosol carbonate) with Mn of5700 da, 15.4 ml (0.19 mol) of pyridine, and 170 mL of DCM and stirredfor 15 min to get a clear solution. Triphosgene (3.3 g, 0.055 0.034 molof phosgene) was dissolved in 20 mL of DCM and the solution wasintroduced into the reaction flask over 2-3 hours. After the additionwas complete, the reaction mixture was stirred for 15 min. To theviscous reaction mixture 200 mL of water was added and stirred for 5min. After allowing the layers to separate, the top aqueous layer wasremoved and discarded. The washing was repeated with two additional 200mL portions of DI water. The reaction mixture was then precipitated with300 mL of IPA. The resulting gel was ground twice with 200 mL portionsof IPA in 1 L laboratory blender. The product was isolated by vacuumfiltration and dried in a vacuum oven at 80° C. The polymer had a HPSECpolystyrene equivalent molecular weight of 200 Kda (THF as mobile phase)and glass transition temperature (Tg) of 90° C. ¹H NMR spectrum of thepolymer was in agreement with the structure. The ¹H NMR spectrum of thispolymer was significantly different from the random copolymer obtainedas in example 13, indicative of the blockiness of the tyrosol recurringunits.

Example 16 Preparation of Poly(PrD-di I₂DAT-co-10 weight % DTyCarbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 25 g (0.029 mol) ofPrD-di I₂DAT, 2.78 g (0.010 mol) of DTy, 15.4 ml (0.19 mol) of pyridine,and 170 mL of DCM and stirred for 15 min to get a clear solution.Triphosgene (4.3 g, 0.044 mol of phosgene) was dissolved in 20 mL of DCMand the solution was introduced into the reaction flask over 2-3 hours.After the addition was complete, the 200 mL of water was added to thereaction mixture and stirred for 5 min. After allowing the layers toseparate, the top aqueous layer was removed and discarded. The washingwas repeated with two additional 200 mL portions of DI water. Thereaction mixture was then precipitated with 300 mL of IPA. The resultinggel was ground twice with 200 mL portions of IPA in 1 L laboratoryblender. The product was isolated by vacuum filtration and dried in avacuum oven at 80° C. The polymer had a HPSEC polystyrene equivalentmolecular weight of 200 Kda (THF as mobile phase) and glass transitiontemperature (Tg) of 95° C. ¹H NMR spectrum of the polymer was inagreement with the structure. Compression molding at 205° C. gave auniform transparent film which gave tensile modulus, ultimate tensilestress, and elongation at break respectively of 280 ksi, 10 ksi and200%.

Example 17 Preparation of Tyrosol or Analog-Based AlternatingPolycarbonates

Alternating polymers having regular sequences of tail-tail, head-head,and/or head-tail configurations are disclosed. These polymers aredistinctly different from random polymers having no specific order oftail-tail, head-head, and/or head-tail configurations. Specifically,polycarbonates derived from tyrosol, have three types of carbonatebonds: aromatic-aromatic (also referred to as head-head), mixedaromatic-aliphatic (also referred to as head-tail), andaliphatic-aliphatic (also referred to as tail-tail) as shown below:

Polymers with random sequences of H-H, H-T, or T-T backbone linkages canhave distinctly different properties from those having a regularsequence of backbone linkages.

To create alternating polymers with a regular, alternating sequence ofH-H and T-T bonds, the monomer was reacted with itself to form a dimer.Then, the dimer was subjected to a polymerization reaction. In thisexample, aliphatic dityrosol carbonate and aliphatic tyrosolchloroformate were used as monomers for polycarbonate synthesis.Aliphatic dityrosol carbonate introduces an enzymatic cleavage site dueto the flexibility and steric accessibility of the aliphatic carbonatebond. Reaction steps are outlined below.

(A) Synthesis of Tyrosol Chloroformate

Tyrosol was placed in a three-necked flask equipped with an overheadstirrer under inert atmosphere. Anhydrous tetrahydrofuran was added froma syringe and a solution was obtained while the mixture was stirred. Thesolution was constantly cooled with an ice/water bath. Triphosgene wasdissolved in anhydrous tetrahydrofuran and added dropwise to thereaction vessel. Aliphatic tyrosol chloroformate was obtained over thecourse of one hour. Most of the solvent was evaporated to prepare forthe work-up. Methylene chloride was added to dissolve the residue andexcess tyrosol was filtered off. The solution was cooled in an ice/waterbath. Cooled deionized water was added to remove most of the HCl builtup during the reaction. The two layers were separated and the organicphase was dried over magnesium sulfate. The solvent was evaporated, andafter drying under vacuum aliphatic tyrosol chloroformate was obtainedas an oil.

(B) Synthesis of Aliphatic Dityrosol Carbonate

Aliphatic tyrosol chloroformate (A) and tyrosol were dissolved inanhydrous tetrahydrofuran under nitrogen atmosphere and cooled with anice/water bath. One equivalent of pyridine was added drop-wise using asyringe pump over the course of twelve hours. Then the solvent wasevaporated, and the residue dissolved in methylene chloride. The organicphase was washed 4 times with dilute HCl, 4 times with 5% (w/v) aqueousbicarbonate and twice with brine. The organic layer was dried overmagnesium sulfate. After drying dityrosol carbonate was obtained as awhite solid.

(C) Synthesis of Poly(Tyrosol Carbonate) with Alternating Carbonate BondSequence

Aliphatic dityrosol carbonate is dissolved in methylene chloride undernitrogen atmosphere. Triphosgene is dissolved in methylene chloride andadded drop-wise to the reaction mixture. After the triphosgene addition,pyridine is added drop-wise to the reaction mixture over the course ofseveral hours. Poly(tyrosol carbonate) with alternating carbonate bondsequence is obtained by standard a workup procedure.

(D) Synthesis of Polytyrosol with Controlled Carbonate Bond Sequence

Dityrosol carbonate (x equivalents) and tyrosol carbonate (yequivalents) are dissolved in anhydrous tetrahydrofurane and cooled indry ice/isopropanol bath. Pyridine is added drop-wise over the course ofseveral hours in step 1. Then triphosgene dissolved in anhydroustetrahydrofuran is added drop-wise into the reaction mixture. Thepoly(tyrosol carbonate) with controlled composition of carbonate bondsis obtained through a standard work-up procedure.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, it should be clearly understood thatthe various embodiments of the present invention described herein areillustrative only and not intended to limit the scope of the presentinvention.

Example 18 Preparation of poly(PrDI₂DAT-co-9% tyrosol-co-1% PEG1KCarbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 45 g (51 mmol) ofPrD-di I₂DAT, 4.5 g (33 mol) of tyrosol, 0.5 g (0.50 mmol) of PEG1000,25 g (320 mmol) of pyridine, and 305 mL of DCM and stirred for 15 min toget a clear solution. Triphosgene (8.6 g, 87 mmol of phosgene) wasdissolved in 32 mL of DCM and the solution was introduced into thereaction flask over 2-3 hours. After the addition was complete, thereaction mixture was quenched with a mixture of 135 mL of THF and 15 mLof water. 350 mL of water was added to the reaction mixture and stirredfor 5 min. After allowing the layers to separate, the top aqueous layerwas removed and discarded. The washing was repeated with two additional350 mL portions of DI water. The reaction mixture was then precipitatedwith 500 mL of acetone. The resulting gel was stirred with 500 mL of IPAwhen the gel broke up into fine particles. The particles were groundtwice, isolated by filtration and dried in a vacuum oven at 80° C. Thepolymer had a Mw of 400 Kda and glass transition temperature (Tg) of 92°C. ¹H NMR spectrum of the polymer was in agreement with the structure.Compression molding at 190° C. gave a uniform transparent film whichgave tensile modulus, tensile stress at yield, and elongation at breakof 240 ksi, 9.1 ksi, and 106% respectively.

Example 19 Preparation of poly(I₂DTy-co-10% Tyrosol Carbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 45 g (0.084 mol) ofI₂DTy, 5 g (0.036 mol) of tyrosol, 35.5 g (0.45 mol) of pyridine, and300 mL of DCM and stirred for 15 min to get a clear solution.Triphosgene (12.3 g, 0.125 mol of phosgene) was dissolved in 32 mL ofDCM and the solution was introduced into the reaction flask over 2-3hours. After the addition was complete, the reaction mixture wasquenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL ofwater was added to the reaction mixture and stirred for 5 min Afterallowing the layers to separate, the top aqueous layer was removed anddiscarded. The washing was repeated with two additional 350 mL portionsof DI water. The reaction mixture was then precipitated with 600 mL ofIPA. The resulting gel was ground twice in a 4 L high speed blender. Theprecipitate obtained was isolated by filtration and dried in a vacuumoven at 80° C. The polymer had a Mw of 318 Kda and a glass transitiontemperature (Tg) of 100° C. ¹H NMR spectrum of the polymer was inagreement with the structure. Compression molding at 190° C. gave auniform transparent film. Using similar procedures a copolymer with 15%tyrosol was prepared. The properties of the polymers are set forthbelow:

% tyrosol Tg, ° C. σ, ksi Modulus, ksi Elongation, % 10 100 8.7 234 23915 82 9.0 240 217

Example 20 Preparation of PLLAdiol Using Ethylene Glycol as Initiator(EGPLLAD7K).

Into a 250 mL round bottomed flask were transferred 1.29 g (0.02 mol) ofethylene glycol, 1.44 tg (3.6 mmol) of Sn(II)octoate and 144.1 g (1.0mol) of L-lactide. A large egg-shaped stir bar was introduced into theflask. The flask was maintained under a positive pressure of nitrogenand then immersed into an oil bath maintained at 110° C. and afterheating for 1 h the lactide melted. The temperature was raised to 140°C. and heated with stirring for 4 h. The flask was then removed from theoil bath and allowed to cool to room temperature. To the flask 350 mL ofDCM was added and stirred overnight to dissolve the polymer. The polymersolution was slowly added to 1 L of heptane with stirring. The polymerprecipitated as white crystalline powder which was isolated byfiltration. The precipitate was washed with 250 mL of acetonitrile toremove any unreacted lactide. The product was dried in a vacuum oven at40° C. for 24 h. DSC showed a Tg of 47° C. and melting points at 134° C.(5 J/g) and 148° C. (15.5 J/g). PrDPLLAD7K was similarly prepared using1,3-propanediol as the initiator instead of ethylene glycol.

Example 21 Preparation of poly(PrD-di I₂DAT-co-50% EGPLLAD7K carbonate).

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 30 g (0.034 mol) ofPrD-di I₂DAT, 30 g (0.004 mol) of EGPLLAD7K, 11.4 g (0.145 mol) ofpyridine, and 360 mL of chloroform and stirred for 15 min to get a clearsolution (the solution was slightly cloudy). Triphosgene (3.96 g, 0.04mol of phosgene) was dissolved in 12 mL of chloroform and the solutionwas introduced into the reaction flask over 2-3 hours. After theaddition was complete, the reaction mixture was quenched with a mixtureof 135 mL of THF and 15 mL of water. 350 mL of water was added to thereaction mixture and stirred for 5 min. After allowing the layers toseparate, the top aqueous layer was removed and discarded. The washingwas repeated with two additional 350 mL portions of DI water. Thereaction mixture was then precipitated with 700 mL of IPA. The resultinggel was ground with 550 mL twice in a 4 L blender. The product wasisolated by filtration and dried in a vacuum oven at 80° C. ¹H NMRspectrum of the polymer was in agreement with the structure. Compressionmolding at 190° C. of the obtained 50% EGPLLAD polymer gave a uniformtransparent film.

Using similar procedures, copolymers containing 20% and 65% EGPLLAD werealso prepared. The physical properties of the three polymer samples areset forth below. Other polymers having different physical properties canbe prepared by routine experimentation informed by the guidance providedherein, e.g., by appropriate selection of comonomer content, polymermolecular weight and film preparation procedures.

% EGPLLAD Tg, ° C. σ, ksi Modulus, ksi Elongation, % 20 60 and 110 9.4262 6 50 Tg = 61 8.0 274 162 Tm = 150 65 Tg = 62 7.0 295 5 Tm = 146

Example 22 Preparation of poly(I₂DTy-co-50% EGPLLAD7K Carbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 25 g (0.046 mol) ofI₂DTy, 25 g (0.004 mol) of EGPLLAD, 14.8 g (0.19 mol) of pyridine, and305 mL of DCM and stirred for 15 min to get a clear solution.Triphosgene (5.19 g, 0.053 mol of phosgene) was dissolved in 15 mL ofDCM and the solution was introduced into the reaction flask over 2-3hours. After the addition was complete, the reaction mixture wasquenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL ofwater was added to the reaction mixture and stirred for 5 min. Afterallowing the layers to separate, the top aqueous layer was removed anddiscarded. The washing was repeated with two additional 350 mL portionsof DI water. The reaction mixture was then precipitated with 600 mL ofIPA. The resulting gel was ground twice in a 4 L high speed blender. Theprecipitate obtained was isolated by filtration and dried in a vacuumoven at 80° C. The polymer had a glass transition temperature (Tg) of100° C. ¹H NMR spectrum of the polymer was in agreement with thestructure. Compression molding at 190° C. gave a uniform transparentfilm. Copolymers containing 45% and 60% of EGPLLAD were also preparedusing similar procedures and characterized. The properties of thepolymers are listed in the table below. Using similar procedurescopolymers containing I₂DTE and polyglycolide-diols (PGAD) can beprepared by replacing PLLAD with PGAD in the above polymerization.

% EGPLLAD Tg, ° C. σ, ksi Modulus, ksi Elongation, % 45 62 and 106 8.2275 17 50 62 and 106 8.0 247 106 60 60 7.9 257 188

Example 23 Preparation of poly(I₂DTy-co-50%DTy Carbonate)

In a 1 L 3-necked round-bottomed flask equipped with a mechanicalstirrer, and a liquid addition device were placed 25 g (0.046 mol) ofI₂DTy, 25 g (0.087 mol) of DTy, 43 g (0.55 mol) of pyridine, and 305 mLof DCM and stirred for 15 min to get a clear solution. Triphosgene (14.2g, 0.143 mol of phosgene) was dissolved in 43 mL of DCM and the solutionwas introduced into the reaction flask over 2-3 hours. After theaddition was complete, the reaction mixture was quenched with a mixtureof 135 mL of THF and 15 mL of water. 350 mL of water was added to thereaction mixture and stirred for 5 min After allowing the layers toseparate, the top aqueous layer was removed and discarded. The washingwas repeated with two additional 350 mL portions of DI water. Thereaction mixture was then precipitated with 600 mL of IPA. The resultinggel was ground twice in a 4 L high speed blender. The precipitateobtained was isolated by filtration and dried in a vacuum oven at 80° C.The polymer had a glass transition temperature (Tg) of 68° C.Compression molding at 170° C. gave a uniform transparent film whichgave tensile modulus, tensile stress at yield, and elongation at breakrespectively of 195 ksi, 4.3 ksi, and 473%. Using similar procedurepoly(I₂DTy-co-20%DTy carbonate was prepared.

Example 24 Synthesis of (4-(2-hydroxyethyl) 2,6,-diiodophenol)

Iodination of tyrosol was carried out by adding 200 mL of KICl₂ solution(2M) to 27.6 g (0.2 mol) of tyrosol in 140 mL of 95% ethanol andstirring the resulting solution for 1 h. When treated with 400 mL ofwater, an oil separated which was stirred with 100 mL of 2% sodiumthiosulfate solution for 2 h. The brown solid obtained was dissolved inethanol and treated with charcoal and filtered. The pure diiodotyrosol(4-(2-hydroxyethyl) 2,6,-diiodophenol) was obtained in 65% yield and wascharacterized by hplc and NMR.

Example 25 Synthesis of 4-hydroxyphenethyl3-(4-(4-hydroxyphenoxy)phenyl)-propanoate

Into a 500 mL round bottomed flask fitted with an overhead stirrer, anda modified Dean-stark trap for solvents heavier than water are added 10g (72 mmol) of tyrosol, 30 g (78 mmol) of desaminothyronine, 0.65 g (3.4mmol) of 4-toluenesulfonic acid monohydrate, and 200 mL of1.2-dichloroethane (DCE). A water-cooled reflux condenser is placed ontop of the modified Dean-stark trap and the contents of the flask areheated to reflux while being stirred. The reaction is continued untilapproximately 1.4 mL of water collected in the modified Dean-stark trapabove the DCE and the water collection essentially stopps (about 4 hoursof reflux). The reaction mixture is cooled to room temperature and thecrude product is dissolved in 100 mL of ethyl acetate and washed twicewith 100 mL portions of 5% sodium bicarbonate solution. After dryingover magnesium sulfate the organic layer is concentrated andprecipitated with hexane. The resulting white crystalline solid iscollected by filtration and dried in a vacuum oven at 25° C. The productis characterized by elemental analysis, hplc, and ¹H NMR.

It will be understood by those skilled in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, the various embodiments and examplesof the present invention described herein are illustrative only and notintended to limit the scope of the present invention.

What is claimed is:
 1. A biocompatible polymer, comprising a recurringunit of formula:

wherein: j and k are each independently zero or an integer selected from1 to 6, provided that j and k are not both 0; X¹ and X² are eachindependently bromine (Br) or iodine (I), and y¹ and y² are eachindependently 0, 1, 2, 3, or 4; L¹ is selected from the group consistingof oxygen (—O—), —R⁴—C(═O)—O—, and —O—R^(4a)—O—C(═O)—; wherein R⁴ isselected from the group consisting of C₁-C₃₀ alkylene, C₂-C₃₀alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene; and R^(4a) is selected from the group consisting ofC₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀alkynylarylene, and C₂-C₃₀ heteroarylene; L⁴ is selected from the groupconsisting of a bond, and optionally substituted phenoxy (—C₆H₄—O—); L⁵is selected from the group consisting of a bond and —CH₂—; Q² at eachoccurrence is independently hydrogen or halogen; or two adjacent Q² forma double bond when adjacent Qs are present; or Z² and an adjacent Q²form a double bond; Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶,—C(O)OR⁷ or —C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a doublebond; wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at eachoccurrence selected from the group consisting of hydrogen, alkyl, aryl,alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl, wherein thenon-hydrogen groups contain up to 30 carbon atoms, wherein theheteroalkyl group contains from 1 to 10 heteroatoms independentlyselected from O, N and S, and the heteroalkylaryl group contains from 1to 3 heteroatoms independently selected from O, N and S; and wherein A¹is selected from the group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀alkyl, C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.
 2. A biocompatible polymer,comprising a recurring unit of formula:

wherein: j and k are each independently zero or an integer selected from1 to 6, provided that j and k are not both 0; X¹ and X² are eachindependently bromine (Br) or iodine (I), and y¹ and y² are eachindependently 0, 1, 2, 3, or 4; L¹ is selected from the group consistingof oxygen (—O—), —R⁴—C(═O)—O—, and —O—R^(4a)—O—C(═O)—; wherein R⁴ isselected from the group consisting of C₁-C₃₀ alkylene, C₂-C₃₀alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene; and R^(4a) is selected from the group consisting ofC₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀alkynylarylene, and C₂-C₃₀ heteroarylene; L⁴ is selected from the groupconsisting of a bond, and optionally substituted phenoxy (—C₆H₄—O—); L⁵is selected from the group consisting of a bond and —CH₂—; Q² at eachoccurrence is independently hydrogen or halogen; or two adjacent Q² forma double bond when adjacent Qs are present; or Z² and an adjacent Q²form a double bond; Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶,—C(O)OR⁷ or —C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a doublebond; and wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at eachoccurrence selected from the group consisting of hydrogen, alkyl, aryl,alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl, wherein thenon-hydrogen groups contain up to 30 carbon atoms, wherein theheteroalkyl group contains from 1 to 10 heteroatoms independentlyselected from O, N and S, and the heteroalkylaryl group contains from 1to 3 heteroatoms independently selected from O, N and S.
 3. Thebiocompatible polymer of claim 1, wherein L¹ is oxygen and L⁴ is a bond,providing a recurring unit of formula:


4. The biocompatible polymer of claim 2, wherein L¹ is oxygen and L⁴ isa bond, providing a recurring unit of formula:


5. The biocompatible polymer of claim 1, wherein L¹ is oxygen and L⁴ isa bond, and Q² is hydrogen, providing a recurring unit of formula:


6. The biocompatible polymer of claim 2, wherein L¹ is oxygen and L⁴ isa bond, and Q² is hydrogen, providing a recurring unit of formula:


7. The biocompatible polymer of claim 1, wherein L5 is a bond, providinga recurring unit of formula:


8. The biocompatible polymer of claim 2, wherein L5 is a bond, providinga recurring unit of formula:


9. The biocompatible polymer of claim 7, wherein the phenyl groups ofthe recurring unit have the phenolic oxygens in the para-position. 10.The biocompatible polymer of claim 7, wherein L⁴ is a bond, L¹ isoxygen, and Q² and Z² are both hydrogen.
 11. The biocompatible polymerof claim 1, wherein j=k=1, L¹ is oxygen, L⁴ and L⁵ are each a bond, andQ² and Z² are each hydrogen, providing a recurring unit of formula:


12. The biocompatible polymer of claim 2, wherein j=k=1, L¹ is oxygen,L⁴ and L⁵ are each a bond, and Q² and Z² are each hydrogen, providing arecurring unit of formula:


13. The biocompatible polymer of claim 11, wherein X¹ and X² are iodine,and at least one of y1 and y2 is non-zero.
 14. The biocompatible polymerof claim 11, wherein X¹ and X² are iodine, at least one of y1 and y2 is2, and the phenyl groups of the recurring unit have the phenolic oxygensin the para-position.
 15. The biocompatible polymer of claim 11, whichis a polycarbonate and further comprises a second recurring unit ofoptionally iodinated tyrosol.
 16. A biocompatible polyurethanecomprising an optionally iodinated tyrosine or an optionally iodinatedtyrosine ester recurring unit, and a second recurring unit selected fromthe group consisting of HBA (hydroxybenzoic acid), mono-iodinated HBAand di-iodinated HBA.
 17. A biocompatible copolymer comprising therecurring unit of the polymer of claim 1 and further comprising atyrosol recurring unit of the formula:

wherein A¹ is selected from the group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀alkyl, C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.
 18. A biocompatible copolymercomprising the recurring unit of the polymer of claim 1 and furthercomprising a recurring unit of the formula:

wherein R¹⁵ is H or CH₃, r is 1 to about 300, and A¹ is selected fromthe group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀alkyl, C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.
 19. The biocompatible polymeraccording to claim 1, characterized in that said polymer is a blockcopolymer with a macromer of the formula:

wherein B is —O—((CH₂)_(p)—O)_(q)— or —O—(CH₂CH(CH₃)—O)_(q)—; p is aninteger ranging from 1 to about 6, and q is about 5 to about 3000; andA¹ is selected from the group consisting of:

wherein R⁸ is selected from a bond, C₁-C₃₀ alkylene, C₂-C₃₀ alkenylene,C₂-C₃₀ alkynylene; C₁-C₃₀ heteroalkylene, C₂-C₃₀ heteroalkenylene,C₂-C₃₀ heteroalkynylene, C₇-C₃₀ heteroalkylarylene, C₈-C₃₀heteroalkenylarylene, C₈-C₃₀ heteroalkynylarylene, C₇-C₃₀ alkylarylene,C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀ heteroarylene;and wherein R⁹ and R¹⁰ are each independently selected from H, C₁-C₃₀alkyl, C₁-C₃₀ heteroalkyl, C₂-C₃₀ alkenyl, C₂-C₃₀ alkynyl, C₂-C₃₀heteroalkenyl, and C₂-C₃₀ heteroalkynyl.
 20. A biocompatible copolymercomprising the recurring unit of the polymer of claim 1 and furthercomprising a p-hydroxybenzoate recurring unit of the formula:

wherein X¹ is selected from Br and I and y1=0, 1 or
 2. 21. Thebiocompatible polymer of claim 1, characterized by the formula:


22. The biocompatible polymer of claim 1, characterized by the formula:


23. The biocompatible polymer of claim 1, characterized by the formula:


24. The biocompatible polymer of claim 1, characterized by the formula:

wherein R¹⁵═H or CH₃, and r=1 to about
 300. 25. The biocompatiblepolymer of claim 15, characterized by the formula:


26. A diphenol compound having the formula:

wherein: j and k are each independently zero or an integer selected from1 to 6, provided that j and k are not both 0; X¹ and X² are eachindependently bromine (Br) or iodine (I), and y¹ and y² are eachindependently 0, 1, 2, 3, or 4; L¹ is selected from the group consistingof oxygen (—O—), —R⁴—C(═O)—O—, and —O—R^(4a)—O—C(═O)—; wherein R⁴ isselected from the group consisting of C₁-C₃₀ alkylene, C₂-C₃₀alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀ heteroalkylene, C₂-C₃₀heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀ arylene, C₇-C₃₀alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀ alkynylarylene, and C₂-C₃₀heteroarylene; and R^(4a) is selected from the group consisting ofC₁-C₃₀ alkylene, C₂-C₃₀ alkenylene, C₂-C₃₀ alkynylene, C₁-C₃₀heteroalkylene, C₂-C₃₀ heteroalkenylene, C₂-C₃₀ heteroalkynylene, C₆-C₃₀arylene, C₇-C₃₀ alkylarylene, C₈-C₃₀ alkenylarylene, C₈-C₃₀alkynylarylene, and C₂-C₃₀ heteroarylene; L⁴ is selected from the groupconsisting of a bond, and optionally substituted phenoxy (—C₆H₄—O—); L⁵is selected from the group consisting of a bond and —CH₂—; Q² at eachoccurrence is independently hydrogen or halogen; or two adjacent Q² forma double bond when adjacent Qs are present; or Z² and an adjacent Q²form a double bond; Z² is hydrogen, —N(R^(x))C(═O)R⁵, —N(R^(x))COOR⁶,—C(O)OR⁷ or —C(O)NR^(x)R^(y), or Z² and an adjacent Q² form a doublebond; and wherein R⁵, R⁶, R⁷, R^(x) and R^(y) are independently at eachoccurrence selected from the group consisting of hydrogen, alkyl, aryl,alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl, wherein thenon-hydrogen groups contain up to 30 carbon atoms, wherein theheteroalkyl group contains from 1 to 10 heteroatoms independentlyselected from O, N and S, and the heteroalkylaryl group contains from 1to 3 heteroatoms independently selected from O, N and S.
 27. Thediphenol compound of claim 26, wherein the phenolic hydroxy groups arein the para-position, providing a compound having the formula:


28. The diphenol compound of claim 26, wherein L⁵ is a bond.
 29. Thediphenol compound of claim 26, wherein L⁴ and L⁵ are each a bond, L¹ isoxygen, Z² is hydrogen and Q² is hydrogen.
 30. The diphenol compound ofclaim 26, wherein L⁴ and L⁵ are each a bond, L¹ is oxygen, Z² ishydrogen, Q² is hydrogen and k=j=1.
 31. The diphenol compound of claim26, wherein L⁴ and L⁵ are each a bond, L¹ is oxygen, Q² and Z² are bothhydrogen, k=j=1, X¹ and X² are iodine, and at least one of y1 and y2 isnon-zero.
 32. A polymer composition comprising the biocompatible polymerof claim
 1. 33. A medical device comprising the biocompatible polymer ofclaim
 1. 34. The medical device of claim 33 further comprising abiologically active compound incorporated into the biocompatiblepolymer.
 35. The medical device of claim 34 wherein said biologicallyactive compound is selected from the group consisting ofchemotherapeutic agents, non-steroidal anti-inflammatory agents,steroidal anti-inflammatory agents, and wound healing agents.
 36. Themedical device of claim 33 which is a stent.
 37. A stent comprising thebiocompatible polymer of claim 1.